Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer MINIREVIEW British Journal of Cancer (2017) 117, 451–460 | doi: 10.1038/bjc.2017.220 Keywords: immune cells; tumour microenvironment; prognostic markers; cancer HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer 1 ,1 Tristan A Barnes and Eitan Amir Department of Medical Oncology and Hematology, Princess Margaret Cancer, Toronto, ON M5G 2M9, Canada Interactions between immune and malignant cells have been known to have clinical relevance for decades. The potential for immune control is now being therapeutically enhanced with checkpoint inhibitors and other novel agents to improve outcomes in cancer. The importance of the immune infiltrate as a prognostic marker is increasingly relevant. In this minireview, we present an overview of the immune infiltrate and its spatial organisation, and summarise the prognostic value of immune cells in different cancer types. International collaborative efforts are standardising histopathologic reporting of the immune infiltrate, to allow application of these parameters in the clinical and research settings. In general terms, a ‘pro-inflammatory’ tumour microenvironment and infiltrating CD8-expressing T lymphocytes are associated with improved clinical outcomes in a broad range of tumour types. The inhibitory function of other immune cells, for example, myeloid-derived suppressor cells and regulatory T cells, appear to have a major role in disrupting the capacity for the immune control of cancers. The immune system and malignant cells interact via a complex immune cells is also now recognised as contributing to the complex network. The importance of immune function in tumour immune response in cancer, some of which promote tumour development and control has been acknowledged for decades. As control and others facilitate cancer progression (Table 1; Figure 1). immunotherapy enters clinical practice, these underpinnings have more relevance as we try to identify predictive biomarkers for benefit from new therapies. The seminal papers describing the LOCATION AND SPATIAL ORGANISATION OF THE ‘hallmarks of cancer’ pronounced the capacity to avoid immune IMMUNE CELL INFILTRATE destruction as one of the requirements for malignancy (Hanahan and Weinberg, 2011). There is now a vast literature supporting Although the distinction between peritumoural, stromal and immunosurveillance as a significant contributor to the natural intratumoural lymphocytes is made histopathologically (Table 2), history of malignancy. The interaction between tumours and the this is likely an artificial segregation as this is a dynamic network that immune system has been described in three scenarios of allows chemokine-generated cell movement between these areas. ‘immunoediting’ (Schreiber et al, 2011); specifically: elimination A qualitative description of the interplay between tumour and (where immune surveillance successfully eradicates malignant immune cell infiltrate has been termed the ‘immune contexture’, cells); equilibrium (where the immune system exerts control over and includes the location of specific immune cells, tertiary abnormal cells) and escape (where tumour cells evade immune lymphoid structures (ectopic lymphoid aggregates that are mechanisms allowing growth and metastasis) (Mittal et al, 2014). generated during immune stimulation and exhibit structural In this mini-review, we aim to define the immune infiltrate and its characteristics of lymphoid organs), and the chemokines and spatial organisation as well as summarising the prognostic value of cytokines involved in this microenvironmental organisation immune cells in different solid cancers. (Fridman et al, 2011). Methods for describing the immune infiltrate are a limitation of current pathological reporting. There remains a lack of consensus regarding reporting of tumour- SUBTYPES OF IMMUNE CELL INFILTRATE infiltrating lymphocytes (TILs), including methods to subtype the infiltrating cells and their spatial organisation. International Historically, studies have focused on the interaction between working groups are trying to create and validate reporting cytotoxic T lymphocytes and cancer cells. The role of other guidelines (Salgado et al, 2015). Immunophenotyping of the *Correspondence: Dr E Amir; E-mail: eitan.amir@uhn.ca Received 15 December 2016; revised 25 May 2017; accepted 1 June 2017; published online 13 July 2017 r The Author(s) named above Published by Springer Nature on behalf of Cancer Research UK. 451 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer Table 1. Cell types in the tumour immune infiltrate Expression Function Lymphoid Cytotoxic T lymphocyte CD3, CD8 Recognise and lyse target cells through release of perforin and granzymes. Activated by dendritic cell antigen presentation via major histocompatibility complex (MHC) Class I antigen to T cell receptor. Apoptosis is induced in cells expressing specific antigen Regulatory T lymphocyte (also CD3, CD4, Serve to maintain tolerant to self antigens; inhibit dendritic cell function of antigen presentation and thus called suppressor T cells) CD25, FOXP3 inhibits both the expansion and the differentiation of T effector cells. Polyclonal Tregs appear to modulate differentiation and cell trafficking T helper lymphocyte (Th cell) CD4 Help to modulate immune responses. Activate and promote growth of cytotoxic T cells; maximise activity of phagocytes through interaction with MHC Class II; role in B cell antibody class switching (e.g., from immunoglobulin-M to immunoglobulin-G) Natural killer cell (NK) CD16, CD56 A subset of cytotoxic lymphocytes that can be activated in the absence of MHC Class I antigen presentation, thus an important component of the innate immune system Myeloid Dendritic cells CD40 Act to process and present antigen on MHC Class I, and via co-stimulatory molecules they serve to activate T lymphocytes Myeloid-derived suppressor cells CD11b, CD66b Pathologically activated immature myeloid cells, with morphological and phenotypical similarity to (MDSC) mononuclear and polymorphonuclear cells. Prevent activation of T cells and have a role in promoting tumour growth and metastasis Macrophages CD68 Part of the innate immune defence with phagocytic capacity, and also have a role in adaptive immunity through activation of other immune cells via cytokine release. M1 macrophages are pro-inflammatory (largely driven by interferon (IFN)-gamma); M2 macrophages release anti-inflammatory cytokines such as IL4, IL10, TGF-beta and nuture tolerance Activating Inhibitory CD4 helper cell (Th1 cell) CD40 CD8 IL2 + + CD25 , FOXP3 OX40 Regulatory T lymphocyte IFNγ ADO receptor IL4 TIM3 IL10 Inhibitory + – + IFNγ TGFβ cytokines CD8 cytotoxic TNFα LAG3 CD28 T lymphocyte + CTLA4 CD40 CD80 PD1 PD1/PDL1 Tumour B7 Myeloid-derived antigen Dendritic cell suppressor cell Tumour cell Figure 1. Pathways affecting cytotoxic T lymphocyte activity within the tumour microenvironment. Table 2. Location of the immune infiltrate Infiltrate Location Intratumoural Within the mass (or nest) of malignant cells, with direct proximity between cancer and immune cells Stromal In the surrounding connective tissues and blood vessels Peritumoural Around the tumour and can refer to cells at the advancing margin of the tumour, in the stroma or the tissues adjacent to the tumour immune infiltrate by immunohistochemistry or immunofluores- of immune co-regulated genes may help to identify and cence staining can be performed in tissue samples, or after characterise the immune infiltrate (Stoll et al, 2015). Meta- generation of cell suspensions that are generated by mechanical or analytical data suggest that in most cancers, the immune infiltrate enzymatic breakdown of fresh tumour tissue (Stoll et al, 2015). The is heterogeneous and there is limited reproducibility of leukocyte use of sectioned tissue specimens allows spatial understanding of subtypes (Stoll et al, 2015). Although the presence of T cells is cell position relative to tumour cells, however, similar to the use of clearly important, the interplay between tumour antigens and cell suspension, is limited by challenges in antigen retrieval major histocompatibility complex (MHC) molecules for antigen (capacity to bind identifying/specific proteins of interest) and poor presentation is critical for efficient T cell activation. High affinity of standardisation. Novel approaches such as mRNA characterisation the targeted peptides for MHC is required for strong stimulation of 452 www.bjcancer.com | DOI:10.1038/bjc.2017.220 Prognostic role of immune cells in cancer BRITISH JOURNAL OF CANCER T cells to secrete cytokines and produce tumour eradication or only appear to translate into improved longer term outcomes in control (Engels et al, 2013). The specific antigenicity of coding non-luminal tumours. exons in mutated cancer genes is an area of research and the A meta-analysis of 25 published studies comprising over 22 000 capacity to sequence whole genomes with greater speed and patients, failed to show that immune infiltrates are associated with reduced cost is enhancing the capacity to identify potentially overall survival (OS) in unselected breast cancer patients, but did antigenic mutations. find such an association in TNBC (hazard ratio (HR): 0.79; 95% confidence interval (CI): 0.71–0.87). CD8-expressing lymphocytes were associated with improved disease-free survival (DFS; HR: 0.69; 95% CI: 0.56–0.84) and breast cancer-specific survival (HR: PROGNOSTIC VALUE OF INFILTRATING IMMUNE CELLS 0.78; 95% CI: 0.71–0.86) in the overall population, whereas the FOXP3-expressing lymphocytes were associated with worse DFS The prognostic value of lymphocytes in stromal, peritumoural and (HR: 1.47; 95% CI: 1.06–2.05) and OS (HR: 1.50; 95% CI: intratumoural locations remains unclear, with conflicting data from 1.15–1.97, P¼ 0.004) (Mao et al, 2016). different tumour sites. Peritumoural lymphocytes at the advancing Clinical trials have not reported an association between TIL, tumour margin and those in direct contact with tumour cells have nuclear grade or histopathological grade in TNBC with most been purported to carry the most prognostic weight particularly in making the assumption that TNBC are high grade (Adams et al, some disease sites (see below). In general terms, a ‘pro-inflamma- 2014). It remains uncertain whether this association may be tory’ tumour microenvironment and infiltrating CD8-expressing T explained partly by response to chemotherapy; lower grade luminal lymphocytes are associated with improved clinical outcomes in a tumours have lesser response to cytotoxic therapy and are less broad range of tumour types. In contrast, the inhibitory function of frequently associated with infiltrating immune cells. other immune cells, for example, myeloid-derived suppressor cells A Th1 immune phenotype and mRNA profiles consistent with and regulatory T cells (Tregs) appear to have a major role in immune activation have also been associated with response to disrupting the capacity for the immune control of cancers and are neoadjuvant chemotherapy (Denkert et al, 2015). There is more therefore associated with worse outcome. variability in results seen in trials reporting outcome for CD4- Perhaps counter-intuitively, favourable outcomes have also been expressing T lymphocytes and FOXP3-expressing Tregs. The observed in tumours infiltrated by inhibitory immune cells, for presence of Tregs prior to chemotherapy is associated with higher example, forkhead box P3-positive regulatory T cells (FOXP3) cells probability of attaining a pathological complete response (pCR), in colorectal cancer. This may represent a feedback loop in the which probably reflects their association with a higher number of context of an existing anti-tumour immune response and thus CD8-expressing cells. A high ratio of CD8:FOXP3 cells and a lower actually indicate increased tumour immunogenicity (Gajewski proportion of FOXP3 at the end of neoadjuvant chemotherapy may et al, 2013). Myeloid-derived suppressor cells (MDSC) and have a more meaningful prognostic value (Dushyanthen et al, 2015). tumour-associated macrophages are both capable of negative The current working group have recommended semi-quantita- regulation of innate and adaptive immune pathways. MDSCs have tive assessment of stromal TILs and at this stage do not advocate a role in tumour growth and metastasis via promotion of immune for sub-classification of lymphocytes (Salgado et al, 2015). This is privilege (ability to tolerate the introduction of antigens without due to both the greater reproducibility of stromal TIL measure- eliciting an inflammatory immune response), tumour microenvir- ment compared with intratumoural TILs, which are difficult to onment remodelling, establishment of a pre-metastatic niche distinguish from malignant cells in standard H&E sections, and the (a scenario where non-cancer cells promote future metastasis) fact that in TNBC and HER2-positive breast cancer, the prognostic and interaction with tumour to promote differentiation, invasion power of TILs persists among all subtypes of infiltrating immune and angiogenesis (Marvel and Gabrilovich, 2015). There is cells (Salgado et al, 2015). evidence that MDSC expansion is associated with more advanced stages of malignancy in multiple cancer types and also correlates Colorectal cancer. Several scoring systems have been proposed for with poor prognosis independent of tumour burden (Ugel et al, quantifying the inflammatory response in colorectal cancer. These 2015). Paradoxically, anti-tumour immunity also leads to selective include the Jass score, the Immunoscore and the Klintrup–Ma¨kinen pressure on malignant cells, which ultimately leads to survival of grade of overall peritumoural inflammation (Park et al, 2014). There tumour cells with reduced immunogenicity (Shankaran, 2001). is evidence that TILs are associated with greater prognostic value There are also data supporting the hypothesis that tumour- than the American Joint Committee on Cancer TNM stage (Jochems infiltrating immune cells can promote invasion and metastases and Schlom, 2011). In a meta-analysis of nine trials examining (Man et al, 2013), which may in part explain the heterogeneity of tumour inflammation in colorectal cancer, the pooled HR confirmed results between studies examining this topic. an OS benefit for patients with prominent TILs compared with those without, with a HR of 0.59 (95% CI: 0.48–0.72, Po0.001) and a HR for cancer-specific survival of 0.40 (95% CI: 0.27–0.61, Po0.001). TUMOUR-SPECIFIC PROGNOSTIC VALUE There were differences between all the studies in the thresholds used to determine TIL positivity of tumours, for example, some used Breast cancer. In breast cancer, the presence of TILs is associated mean or median cut offs, others used high vs low scores of Klintrup– with improved prognosis in human epidermal growth factor Makinen or Jass scores (Mei et al, 2014). The evaluation of T cell receptor 2 (HER2) positive and triple negative breast cancers subsets and specific location of lymphocytic infiltrate did not show (TNBC), but not in luminal subtypes. In addition, the recognition strong prognostic value, specifically CD3, CD8, FOXP3 and at of the prognostic value of the immune infiltrate has been the basis different sites (tumour centre, peritumoural stroma and invasive for establishing a breast cancer immunological grade (Salgado et al, tumour margin) were examined. CD3-positive cells at the invasive 2015). margin had OR for DFS of 0.4 (95% CI: 0.35–0.68) and for OS of Independent of other clinicopathological prognostic factors or 0.63 (95% CI: 0.42–0.93). This analysis was limited by significant chemotherapy regimens, multiple studies have confirmed stromal inter-study heterogeneity (Mei et al, 2014). This contrasts to earlier TILs are associated with higher rates of pathological complete individual study data showing statistically significant association response (pCR) to neoadjuvant chemotherapy in all subgroups between the type of immune cell density at the centre of the tumour evaluated (including ER positive, HER2-positive tumours) or the infiltrating margin and patient outcome (Jochems and (Dushyanthen et al, 2015). However, these differences in response Schlom, 2011). www.bjcancer.com | DOI:10.1038/bjc.2017.220 453 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer Ovarian cancer. In a meta-analysis of 10 studies comprising 1815 infiltrating cells may not be as important as the proportion of patients with treated ovarian carcinoma (Hwang et al, 2012), presence CD8-expressing cells relative to all infiltrating cells. The prognostic of intra-epithelial T lymphocytes was associated with improved OS value of intratumoural CD8-positive lymphocytes appears superior (pooled HR for death 0.45, 95% CI: 0.34–0.58, Po0.001). CD3- and even to the adequacy of surgical debulking in prognosticating for CD8-expressing lymphocytes were both examined, and both both progression free survival and OS (Zhang, 2003). conferred a survival advantage; CD8 was examined more frequently and demonstrated a larger magnitude of effect on OS than CD3 Non-small cell lung cancer. In a meta-analysis of 29 trials with (pooled HR: 0.46 and 0.57, respectively) (Hwang et al, 2012). over 86 000 patients, high levels of CD8-expressing cells infiltrating This positive association between CD8-expressing lymphocytes the tumour or in the tumour stroma of non-small cell lung cancer and clinical outcome is also observed in the assessment of patients (NSCLC) specimens were associated with better OS (HR: 0.76 and before treatment and following neoadjuvant chemotherapy. Data 0.80, respectively) compared with tumours without lymphocytes on CD3-expressing lymphocytes, B cells and NK cells are less clear present. CD3 expression also demonstrated similar findings; (Santoiemma and Powell, 2015). There are conflicting data pooled HR for OS 0.65 (95% CI: 0.50–0.84, P¼ 0.001) for stromal regarding FOXP3-positive Tregs, with a few studies demonstrating CD3 cells and 0.66 (95% CI: 0.45–0.97, P¼ 0.03) for intratumoural superior outcome, but most studies suggesting a negative impact CD3 cells. Presence of intratumoural CD4-expressing cells between on survival outcomes through inhibition of cytotoxic T cell activity the tumour cells resulted in improved OS (HR: 0.65; 95% CI: 0.46– (Santoiemma and Powell, 2015). The measured absolute number of 0.91, P¼ 0.01). Despite a higher effect size, a significant association Table 3. Studies examining the prognostic impact of infiltrating immune cells in melanoma Study Number Result Association Cell type (Kakavand 60 Positive correlation between CD3, CD4 and CD8 cells in sentinel node and DFS/OS; Positive CD3, CD4 and et al, 2015) PD1þ lymphocytes associated with worse outcome association CD8 (Saldanha et al, 655 Higher TILs are associated with better prognosis; confirms value of a simplified numerical Positive TIL 2017) TIL scoring system association (Park and Kim, 177 Density of lymphocytes in the peritumoural and intratumoural regions were both Positive TIL 2017) prognostic association (Obeid et al, 147 Expression of PD-L1 and PD-L2 correlated with increasing densities of immune cells. PD-L2 Positive PD-L2 and TILs 2016) expression associated with improved OS association (Weiss et al, 1241 Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile Positive TILs 2016) and improved prognosis compared with melanomas with non-brisk or absent TILs association (Garg et al, 57 B cells are associated with a significantly better overall survival in patients with cutaneous Positive B cells 2016) primary melanomas of 41 mm Breslow depth association (Bosisio et al, 710 Sheets/clusters of plasma cells associated with worse prognosis than melanomas without Negative Plasma cells 2016) plasma cells association (Messaoudene 39 NK cells in SLN associated with higher risk of relapse; NK cells did not correlate with Negative NK cells et al, 2015) thickness of primary but with patient age association (Fortes et al, 4133 High levels TILs associated with improved OS Positive TIL 2015) association (Song et al, 82 TILs decreased the risk of distant metastases in oral mucosal melanoma Positive TIL 2015) association (Donizy et al, 104 High levels TILs associated with improved OS Positive TIL 2015) association (Eriksson et al, 4237 TILs demonstrated no prognostic value for survival No TIL 2015) association (Thomas et al, 3330 High levels TILs associated with improved OS Positive TIL 2013) association (Cintolo et al, 161 Absence of TIL was associated with worse DSS; In radial growth phase presence of TIL with Positive TIL 2013) regression was associated with a poor prognosis association (Lee et al, 90 Brisk TILs were associated with improved prognosis in acral melanoma Positive TIL 2013) association (Grotz et al, 250 TILs in elderly melanoma patients predicts both SLN metastasis and improved melanoma- Positive TIL 2013) specific outcomes association (Azimi et al, 1865 TIL grade is an independent predictor of OS. Pronounced TIL infiltrate associated with Positive TIL 2012) excellent prognosis association (Erdag et al, 147 Higher densities of CD8þ T cells correlated best with survival, a higher density of CD45þ Positive CD8, CD45, T 2012) leukocytes, T cells, and B cells also correlated with increased survival association cells and B cells (Ladanyi et al, 106 CD20þ B cells most often found in peritumoural stroma, correlated with activated T Positive CD20 B cells and 2011) lymphocytes and high number of these cells provided OS advantage association activated T cells (Knol et al, 102 High Foxp3 expression using qPCR predicts for worse progression free survival in stage III Negative FOXP3 2011) melanoma patients association (Burton et al, 515 TIL response is a significant predictor of SLN metastasis but is not a major predictor of DFS No TIL 2011) or OS association Abbreviations: DFS¼ disease-free survival; DSS¼ disease specific survival; NK¼ natural killer; OS¼ overall survival; SLN¼ sentinal lymph node; TIL¼ tumour-infiltrating lymphocytes. 454 www.bjcancer.com | DOI:10.1038/bjc.2017.220 Prognostic role of immune cells in cancer BRITISH JOURNAL OF CANCER Table 4. Immune cells in renal cell carcinoma Number Study Result Association Cell type patients (Geissler 104 Tumour-infiltrating NK cells and Th1 markers associated with increased OS, for example, Positive association; NK and Th1; T et al, 2015) HLA-DRC and CXCR3C T cells; whereas a high number of T cells, especially with high negative association cells (CD69) CD69 expression correlated with worse prognosis (Kang et al, 199 PD1-positive or FoxP3-positive lymphocytes predicted poor OS survival Negative association FOXP3, 2013) PD1þ lymphocytes (Hotta 105 Low levels of memory T cells had improved OS Negative association Memory T et al, 2015) cells (Eckl et al, 41 NK cell percentage does not provide prognostic information No association NK cells 2012) (Liotta 30 Increase in both peripheral and intratumoural Tregs associated with worse prognosis Negative association Tregs et al, 2011) (Li et al, 125 Increased peritumoural Tregs are associated with worse prognosis in clear cell renal cell Negative association Tregs 2009) carcinoma (Bromwich 73 Increased CD4þ T cells associated with worse cancer-specific survival; no association Negative association CD4 et al, 2003) demonstrated with CD8þ T cells Abbreviations: NK¼ natural killer; OS¼ overall survival. Table 5. Studies of TILs in head and neck squamous cell carcinoma Number Study Result Association Cell type patients (Xu et al, 202 TIL level was an independent positive prognostic factor for DFS Positive TIL 2017) association (Kogashiwa 84 PD-L1 expression was associated with CD8þ tumour-infiltrating lymphocytes and Positive CD8 et al, 2017) better outcome in patients with locally advanced oropharyngeal SCC association (Punt et al, 162 High number of T cells was correlated with improved DFS in HPV-positive Positive T cells, Th17 2016) oropharyngeal SCC; improved outcome correlated with active Th17 cells and lower association IL-17(þ ) non-T cells (Nguyen 278 Higher CD4 levels predicted improved OS and disease-specific survival Positive CD4 et al, 2016) association (Caldeira 28 Increased neutrophilic infiltration demonstrated in tumours with higher T stage; no No association Neutrophils et al, 2015) correlation with survival (Balermpas 161 CD8þ TILs constitute an independent prognostic marker in HNSCC patients treated Positive CD8 et al, with adjuvant chemoradiotherapy; prognostic benefit is apparent in HPV pos and neg association 2016b) subgroups (Partlova 54 HPV-positive tumour showed significantly higher numbers of infiltrating IFNgþ Positive IFNgþ CD8þ T et al, 2015) CD8þ T lymphocytes, IL-17þ CD8þ T lymphocytes, myeloid dendritic cells and are association cells, IL-17 CD8þ T associated with better outcome compared to HPV-negative cells (Wolf et al, 39 CD68þ macrophages were found associated with positive nodes and poorer overall Negative Macrophages 2015) survival (not significant) association (Ward et al, 270 TIL levels prognostic in HPV-positive HNSCC Positive TIL 2014) association (Balermpas 101 High infiltrating CD3þ and CD8þ cells correlate with survival outcomes with Positive CD3þ and CD8þ T et al, 2014) chemoradiation association cells (Nordfors 203 Higher CD8(þ ) TIL counts correlated to a better 3-year OS in HPV pos; no correlation Positive CD8; CD4 et al, 2013) of CD4(þ ) TILs with survival outcomes association; no association (Fraga et al, 70 CD57þ TILs do not correlate with survival outcomes No association CD57 2012) (Wansom 46 T-cell infiltration did not differ by HPV status; related to DSS and OS; after adjusting Positive CD8, FOXP3 and et al, 2012) for HPV status, CD8, FoxP3, and total T cells were significantly associated with DSS association total T cells and OS (Sun et al, 83 Tumour-infiltrating CD4þ CD25(high) Foxp3þ Tregs correlated with intratumoural No association FOXP3 2012) COX-2 expression and were associated with a worse recurrence free survival in univariate but not multivariate analysis (Pretscher 33 Intra-epithelial CD8 cells in metastatic lymph nodes and high CD20þ Bcells in Positive CD8, B cells et al, 2009) lymphoid tissue of lymph node metastases were associated with improved DFS association (Badoual, 84 CD4þ CD69þ T cells are associated with improved OS Positive CD4CD69þ T cells 2006) association Abbreviations: DFS¼ disease-free survival; DSS = disease specific survival; HNSCC = head and neck SCC; OS¼ overall survival; SCC¼ squamous cell carcinoma; TIL¼ tumour-infiltrating lymphocytes. www.bjcancer.com | DOI:10.1038/bjc.2017.220 455 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer between stromal CD4-expressing cells and outcome was not Urothelial cancers. The approval of immunotherapy in the observed (HR 0.43; 95% CI: 0.07–2.61, P¼ 0.36), likely due to treatment of advanced urothelial malignancy suggests the relevance greater heterogeneity. FOXP3-expressing T cells in the tumour of the immune system. This is supported by most studies stroma had association with worse progression-free and OS (HR: demonstrating the positive prognostic value of CD3, CD4 and 2.14; 95% CI: 1.68–2.72; Po0.001) and 2.67 (95% CI: 1.74–4.08; CD8 T cells, and the negative association of FOXP3-positive T cells Po0.001, respectively) (Geng et al, 2015). with survival, see Table 6. Melanoma. Checkpoint inhibitors were first approved in mela- Hepatocellular carcinoma. Several studies have examined the noma after a long history of interest in the immune response to role of the intratumoural and peritumoural (parenchymal) these tumours after observation of spontaneous responses (Mihm infiltrate in hepatocellular carcinoma (HCC) (Table 7). High and Mule, 2015). One histopathological definition of the immune levels of FOXP3 Tregs are associated with worse DFS and OS. response in melanoma categorised the immune infiltrating response Two large meta-analyses performed in 2014 demonstrate the as ‘brisk’, a scenario where lymphocytes are demonstrated in the importance of FOXP3 in both the development and prognosis of entire tumour mass or along the advancing edge; ‘non-brisk’, where HCC (Huang et al, 2014; Zhao et al, 2014). Gabrielson et al, 2016 lymphocytes are seen focally in the centre of the tumour or along applied the Galon Immunoscore (Galon et al, 2014) to HCC and part of the invasive margin; or ‘absent’ with no tumoural confirmed its prognostic value, CD3 and CD8 cell densities lymphocytes at all or lymphocytes seen, but not interacting with predicted recurrence with ORs of 5.8 (95% CI: 1.6–21.8) and 3.9 melanoma cells. These subgroups provide prognostic information in (95% CI: 1.1–14.2), respectively. PDL1 staining was positively historical studies. In one study, melanoma-specific death was 30 and correlated with high CD3 and CD8 density and predicted a lower 50% lower in the non-brisk and brisk groups, respectively, compared rate of recurrence (Gabrielson et al, 2016). The applicability of with the absent group (Mihm and Mule, 2015). In contrast, studies these tools remains limited by routine access to technology to report no survival advantage with lymphocytic infiltrate particularly subtype these T cells. with respect to tumours of earlier stage and not in the radial growth Other tumour types. The prognostic role of the immune infiltrate phase (Ladanyi, 2015). However, overall, there is a large body of evidence documenting the prognostic value of the immune infiltrate in less common malignancies is summarised in the Online Appendix. in melanoma (see summary in Table 3). Renal cell carcinoma. There is contradictory evidence regarding the role of the immune cell infiltrate in renal cell carcinoma. BRAIN METASTASES Multiple studies have demonstrated a worse outcome in patients with a neutrophilic, and/or lymphocytic infiltrate (Jochems and Although the central nervous system (CNS) has been purported to Schlom, 2011), a finding which appears reproducible (Table 4). be an ‘immune privileged’ site, there is an increasing evidence The reasons for this are not clear. supporting the role of immune infiltrating cells in brain tumours. In Head and neck cancer. Several clinical trials have demonstrated a study by Harter et al, TILs in brain metastases from different that tumour infiltration by CD3- and CD8-expressing T cells tumour types were quantified and associated with outcome. This was correlates with improved disease outcome in chemoradiother- then validated in a breast cancer only brain metastases cohort. apy-treated patients with head and neck cancer. This positive Carcinomas demonstrated more frequent stromal infiltration, prognosis holds true regardless of the human papilloma virus whereas TILs in melanoma were more often diffusely infiltrative. (HPV) DNA status (Balermpas et al, 2016a). Smoking-associated High TILs level, high-programed cell death protein (PD)1þ /CD8þ tumours with higher degrees of genomic instability and higher and programed death ligand (PDL)-1 staining were associated with antigenicity would be expected to have increased potential to smaller tumours but there was no significant association with activate an immune response; however, this is not supported by survival demonstrated (Harter et al, 2015). In contrast, Bienkowski clinical evidence. There is conflicting information regarding and Preusser, 2015 provide a review of the literature in which they differences in the immune infiltrate in HPV-positive vs negative concluded that tumour-infiltrating lymphocyte density in CNS status (Wansom et al, 2012; Partlova et al, 2015); see Table 5. metastases were strongly associated with improved OS . Table 6. Studies examining prognostic impact of immune cells in bladder cancer Number Study Result Association Cell type patients (Krpina et al, 115 CD3þ and CD8þ TIL are predictive of bladder cancer recurrence in patients with Positive association CD3 and CD8 2015) solitary low-grade non-muscle invasive bladder cancer (Wang et al, 302 Intratumoural CD103(þ ) TILs inversely associated with tumour size. High CD103þ cells Positive association CD103þ 2015) associated with improved OS. (Zhang et al, 131 Tumour-infiltrating CD4(þ ) T cell density emerged as an independent prognostic factor Positive association CD4 2015) for OS (HR: 2.75; P¼ 0.004) Knief et al 149 FOXP3/CD8 (OS: P¼ 0.013, HR: 1.32, 95% CIs: 1.06–1.65) ratios were significantly Negative association FOXP3/CD8 (2016) associated with briefer OS and time to cancer-specific death ratio (Sjodahl et al, 296 CD3(þ ) TILs was significantly associated with good prognosis. Positive association with Positive association; CD3þ ; High 2014) CD3 was modulated by CD68(þ ) TAMs. Strongest negative association with survival was Negative association CD68/CD3 ratio a high ratio between CD68 and CD3 (Sharma et al, 69 Higher numbers of CD8 TILs within the tumour (4 or ¼ 8) had better DFS and OS Positive association CD8 2007) (Hilmy et al, 103 No correlation between TIL level and prognosis No association TILs 2006) Abbreviations: TAM¼ tumour-associated macrophage; OS¼ overall survival; TIL¼ tumour-infiltrating lymphocytes. 456 www.bjcancer.com | DOI:10.1038/bjc.2017.220 Prognostic role of immune cells in cancer BRITISH JOURNAL OF CANCER Table 7. Studies examining prognostic value in HCC Number Study Result Association Cell type patients (Sideras 154 Low CD8þ TIL associated with poor HCC-specific survival. Positive CD8 et al, 2017) association (Gabrielson 65 Intratumoural and peri-tumoural CD3þ /CD8þ density associated with lower risk of Positive CD3/CD8 ratio et al, 2016) recurrence association (Tu et al, 57 FOXP3þ Tregs/CD4þ T cells ratio was an independent prognostic factor for OS Positive FOXP3/CD4 ratio 2016) association (Wang et al, 66 Tumour CD4 and CD8 lower than non-neoplastic liver; high Foxp3 associated with poor Negative FOXP3 2016) OS, whereas low CD8 expression in non-neoplastic liver associated with high HCC association recurrence rate. (He et al, 149 High neutrophil to lymphocyte ratio in peritumoural tissues correlated with poor Negative Neutrophil:lymphocyte 2015) prognosis in patients with HCC association ratio (Sun et al, 449 CD8þ in tumour centre had highest prognostic impact on DFS and OS Positive CD8 2015) association (Ozgur et al, 8 High FoxP3þ poorer DFS Negative FOXP3 2014) association (Brunner 119 IL-33 and CD8þ cells associated with prolonged OS Positive IL-33 and CD8 et al, 2015) association (Huang 1964 OS significantly lower in high FOXP3 infiltrated tumours than low (at 1, 3 and 5 years) Positive FOXP3 et al, 2014) (meta-analysis 13 studies) association Abbreviations: HCC¼ hepatocellular carcinoma; OS¼ overall survival; TIL¼ tumour-infiltrating lymphocytes. Summary. Broadly speaking, the immune infiltrate can be Badoual C (2006) Prognostic value of tumor-infiltrating CD4þ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12: 465–472. classified as a ‘pro-inflammatory’ phenotype with infiltrating T Balermpas P, Michel Y, Wagenblast J, Seitz O, Weiss C, Rodel F, Rodel C, cells and a cytokine profile consistent with immune activation. Fokas E (2014) Tumour-infiltrating lymphocytes predict response to Immune control of tumours can occur spontaneously, and the definitive chemoradiotherapy in head and neck cancer. Br J Cancer 110(2): presence of an immune infiltrate is generally a good prognostic 501–509. sign. However, the immune infiltrate has variable effect in Balermpas P, Ro¨del F, Ro¨del C, Krause M, Linge A, Lohaus F, Baumann M, prognostic models depending on the tumour type, location of Tinhofer I, Budach V, Gkika E, Stuschke M, Avlar M, Grosu A-L, the cells and state of activation; the complexity of immune Abdollahi A, Debus J, Bayer C, Stangl S, Belka C, Pigorsch S, Multhoff G, networks are likely oversimplified in current measurement models. Combs SE, Monnich D, Zips D, Fokas E (2016a) CD8þ tumour- Tumour evasion through inhibitory mechanisms may serve as a infiltrating lymphocytes in relation to HPV status and clinical outcome in predictive marker for benefit from immunotherapy, which inhibits patients with head and neck cancer after postoperative negative regulators of the immune system. Alternatively, the chemoradiotherapy: a multicentre study of the German cancer consortium microenvironment may lack immune cell infiltration, and tumour radiation oncology group (DKTK-ROG). Int J Cancer 138(1): 171–181. resistance is likely through immune system ignorance (Gajewski Balermpas P, Rodel F, Rodel C, Krause M, Linge A, Lohaus F, Baumann M, Tinhofer I, Budach V, Gkika E, Stuschke M, Avlar M, Grosu AL, et al, 2013), and therefore promoting immune activation is less Abdollahi A, Debus J, Bayer C, Stangl S, Belka C, Pigorsch S, Multhoff G, likely to be successful in this setting. Combs SE, Monnich D, Zips D, Fokas E (2016b) CD8þ tumour- For tumour-infiltrating immune cells to live up to the ‘hype’ of infiltrating lymphocytes in relation to HPV status and clinical outcome in inducing and promoting long-term tumour control and contribute patients with head and neck cancer after postoperative as valuable prognostic markers, their subtype (especially activated chemoradiotherapy: a multicentre study of the German cancer consortium antigen specific cytotoxic T lymphocytes) and position (organised radiation oncology group (DKTK-ROG). Int J Cancer 138(1): 171–181. spatial response) need to be defined and measured in a standardised Bienkowski M, Preusser M (2015) Prognostic role of tumour-infiltrating manner. Successful inclusion of immune cell markers in prognostic inflammatory cells in brain tumours: literature review. Curr Opin Neurol clinical models is becoming a realistic hope in some cancers. 28(6): 647–658. Bosisio FM, Wilmott JS, Volders N, Mercier M, Wouters J, Stas M, Blokx WAM, Massi D, Thompson JF, Scolyer RA, van Baren N, van den Oord JJ CONFLICT OF INTEREST (2016) Plasma cells in primary melanoma. Prognostic significance and possible role of IgA. Mod Pathol 29(4): 347–358. Bromwich EJ, McArdle PA, Canna K, McMillan DC, McNicol A, Brown M, The authors declare no conflict of interest. Aitchison M (2003) The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer. Br J Cancer 89(10): 1906–1908. REFERENCES Brunner SM, Rubner C, Kesselring R, Martin M, Griesshammer E, Ruemmele P, Stempfl T, Teufel A, Schlitt HJ, Fichtner-Feigl S (2015) Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Tumor-infiltrating, interleukin-33-producing effector-memory CD8(þ ) Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, T cells in resected hepatocellular carcinoma prolong patient survival. Sledge GW, Sparano JA, Badve SS (2014) Prognostic value of tumor- Hepatology 61(6): 1957–1967. infiltrating lymphocytes in triple-negative breast cancers from two phase Burton AL, Roach BA, Mays MP, Chen AF, Ginter BA, Vierling AM, III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. Scoggins CR, Martin RC, Stromberg AJ, Hagendoorn L, McMasters KM J Clin Oncol 32(27): 2959–2966. (2011) Prognostic significance of tumor infiltrating lymphocytes in melanoma. Am Surg 77(2): 188–192. Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, Saw RP, Thompson JF (2012) Tumor-infiltrating lymphocyte grade is an Caldeira PC, de Andrade Sousa A, de Aguiar MC (2015) Differential independent predictor of sentinel lymph node status and survival in infiltration of neutrophils in T1-T2 versus T3-T4 oral squamous cell patients with cutaneous melanoma. J Clin Oncol 30(21): 2678–2683. carcinomas: a preliminary study. BMC Res Notes 8: 569. www.bjcancer.com | DOI:10.1038/bjc.2017.220 457 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer Cintolo JA, Gimotty P, Blair A, Guerry D, Elder DE, Hammond R, Elenitsas R, Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Xu X, Fraker D, Schuchter LM, Czerniecki BJ, Karakousis G (2013) Local Cell 144(5): 646–674. immune response predicts survival in patients with thick (t4) melanomas. Harter PN, Bernatz S, Scholz A, Zeiner PS, Zinke J, Kiyose M, Blasel S, Ann Surg Oncol 20(11): 3610–3617. Beschorner R, Senft C, Bender B, Ronellenfitsch MW, Wikman H, Denkert C, Gv Minckwitz, Brase JC, Sinn BV, Gade S, Kronenwett R, Glatzel M, Meinhardt M, Juratli TA, Steinbach JP, Plate KH, Wischhusen J, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Weide B, Mittelbronn M (2015) Distribution and prognostic relevance of Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, Andre F, tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune Klauschen F, Blohmer J-U, Krappmann K, Schmidt M, Tesch H, checkpoints in human brain metastases. Oncotarget 6(38): 40836–40849. Ku¨mmel S, Sinn P, Jackisch C, Dietel M, Reimer T, Untch M, Loibl S He G, Zhang H, Zhou J, Wang B, Chen Y, Kong Y, Xie X, Wang X, Fei R, (2015) Tumor-infiltrating lymphocytes and response to neoadjuvant Wei L, Chen H, Zeng H (2015) Peritumoural neutrophils negatively chemotherapy with or without carboplatin in human epidermal growth regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in factor receptor 2–positive and triple-negative primary breast cancers. hepatocellular carcinoma. J Exp Clin Cancer Res 34: 141. J Clin Oncol 33(9): 983–991. Hilmy M, Campbell R, Bartlett JMS, McNicol AM, Underwood MA, Donizy P, Kaczorowski M, Halon A, Leskiewicz M, Kozyra C, Matkowski R McMillan DC (2006) The relationship between the systemic inflammatory (2015) Paucity of tumor-infiltrating lymphocytes is an unfavorable response, tumour proliferative activity, T-lymphocytic infiltration and prognosticator and predicts lymph node metastases in cutaneous COX-2 expression and survival in patients with transitional cell carcinoma melanoma patients. Anticancer Res 35(1): 351–358. of the urinary bladder. Br J Cancer 95(9): 1234–1238. Dushyanthen S, Beavis PA, Savas P, Teo ZL, Zhou C, Mansour M, Darcy PK, Hotta K, Kato Y, Leighl N, Takigawa N, Gaafar RM, Kayatani H, Hirata T, Loi S (2015) Relevance of tumor-infiltrating lymphocytes in breast cancer. Ohashi K, Kubo T, Tabata M, Tanimoto M, Kiura K (2015) Magnitude of BMC Med 13: 202. the benefit of progression-free survival as a potential surrogate marker in Eckl J, Buchner A, Prinz PU, Riesenberg R, Siegert SI, Kammerer R, Nelson PJ, phase 3 trials assessing targeted agents in molecularly selected patients Noessner E (2012) Transcript signature predicts tissue NK cell content with advanced non-small cell lung cancer: systematic review. PLoS One and defines renal cell carcinoma subgroups independent of TNM staging. 10(3): e0121211. J Mol Med 90(1): 55–66. Huang Y, Liao H, Zhang Y, Yuan R, Wang F, Gao Y, Wang P, Du Z (2014) Engels B, Engelhard Victor H, Sidney J, Sette A, Binder David C, Liu Rebecca B, Prognostic value of tumor-infiltrating FoxP3þ T cells in gastrointestinal Kranz David M, Meredith Stephen C, Rowley Donald A, Schreiber H cancers: a meta analysis. PLoS ONE 9(5): e94376. (2013) Relapse or eradication of cancer is predicted by peptide-major Hwang W-T, Adams SF, Tahirovic E, Hagemann IS, Coukos G (2012) histocompatibility complex affinity. Cancer Cell 23(4): 516–526. Prognostic significance of tumor-infiltrating T-cells in ovarian cancer: a Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM, Dengel LT, meta-analysis. Gynecol Oncol 124(2): 192–198. Patterson JW, Slingluff CL (2012) Immunotype and immunohistologic Jochems C, Schlom J (2011) Tumor-infiltrating immune cells and prognosis: characteristics of tumor infiltrating immune cells are associated with the potential link between conventional cancer therapy and immunity. Exp clinical outcome in metastatic melanoma. Cancer Res 72(5): 1070–1080. Biol Med 236(5): 567–579. Eriksson H, Frohm-Nilsson M, Ja¨rås J, Kanter-Lewensohn L, Kjellman P, Kakavand H, Vilain RE, Wilmott JS, Burke H, Yearley JH, Thompson JF, Månsson-Brahme E, Vassilaki I, Hansson J (2015) Prognostic factors in Hersey P, Long GV, Scolyer RA (2015) Tumor PD-L1 expression, immune localized invasive primary cutaneous malignant melanoma: results of a cell correlates and PD-1þ lymphocytes in sentinel lymph node melanoma large population-based study. Br J Dermatol 172(1): 175–186. metastases. Mod Pathol 28(12): 1535–1544. Fortes C, Mastroeni S, Mannooranparampil TJ, Passarelli F, Zappala A, Kang MJ, Kim KM, Bae JS, Park HS, Lee H, Chung MJ, Moon WS, Lee DG, Annessi G, Marino C, Caggiati A, Russo N, Michelozzi P (2015) Tumor- Jang KY (2013) Tumor-infiltrating PD1-positive lymphocytes and infiltrating lymphocytes predict cutaneous melanoma survival. Melanoma FoxP3-positive regulatory T cells predict distant metastatic relapse and Res 25(4): 306–311. survival of clear cell renal cell carcinoma. Transl Oncol 6(3): 282–289. Fraga CA, de Oliveira MV, Domingos PL, Botelho AC, Guimaraes AL, Knief J, Reddemann K, Petrova E, Herhahn T, Wellner U, Thorns C (2016) Teixeira-Carvalho A, Correa-Oliveira R, De Paula AM (2012) Infiltrating High density of tumor-infiltrating B-lymphocytes and plasma cells CD57þ inflammatory cells in head and neck squamous cell carcinoma: signifies prolonged overall survival in adenocarcinoma of the clinicopathological analysis and prognostic significance. Appl esophagogastric junction. Anticancer Res 36(10): 5339–5345. Immunohistochem Mol Morphol 20(3): 285–290. Knol AC, Nguyen JM, Quereux G, Brocard A, Khammari A, Dreno B (2011) ` ` Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G Prognostic value of tumor-infiltrating Foxp3þ T-cell subpopulations in (2011) Prognostic and Predictive Impact of Intra- and Peritumoral metastatic melanoma. Exp Dermatol 20(5): 430–434. Immune Infiltrates. Cancer Res 71(17): 5601–5605. Kogashiwa Y, Yasuda M, Sakurai H, Nakahira M, Sano Y, Gonda K, Ikeda T, Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, Reddy S, Inoue H, Kuba K, Oba S, Ishikawa J, Enoki Y, Matsumura S, Minami K, Kleiner D, Fishbein T, Johnson L, Island E, Satoskar R, Banovac F, Jha R, Ebihara Y, Sugasawa M (2017) PD-L1 expression confers better prognosis Kachhela J, Feng P, Zhang T, Tesfaye A, Prins P, Loffredo C, Marshall J, in locally advanced oral squamous cell carcinoma. Anticancer Res 37(3): Weiner L, Atkins M, He AR (2016) Intratumoral CD3 and CD8 T-cell 1417–1424. densities associated with relapse-free survival in HCC. Cancer Immunol Krpina K, Babarovic E, Jonjic N (2015) Correlation of tumor-infiltrating Res 4(5): 419–430. lymphocytes with bladder cancer recurrence in patients with solitary Gajewski TF, Schreiber H, Fu Y-X (2013) Innate and adaptive immune cells in low-grade urothelial carcinoma. Virchows Archiv 467(4): 443–448. the tumor microenvironment. Nat Immunol 14(10): 1014–1022. Ladanyi A (2015) Prognostic and predictive significance of immune cells Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C (2014) infiltrating cutaneous melanoma. Pigment Cell Melanoma Res 28(5): Towards the introduction of the ‘Immunoscore’ in the classification of 490–500. malignant tumours. J Pathol 232: 199–209. Ladanyi A, Kiss J, Mohos A, Somlai B, Liszkay G, Gilde K, Fejos Z, Gaudi I, Garg K, Maurer M, Griss J, Bruggen MC, Wolf IH, Wagner C, Willi N, Dobos J, Timar J (2011) Prognostic impact of B-cell density in cutaneous Mertz KD, Wagner SN (2016) Tumor-associated B cells in cutaneous melanoma. Cancer Immunol Immunother 60(12): 1729–1738. primary melanoma and improved clinical outcome. Hum Pathol 54: Lee S-J, Lim HJ, Choi YH, Chang YH, Lee WJ, Kim DW, Yoon GS (2013) The 157–164. clinical significance of tumor-infiltrating lymphocytes and microscopic Geissler K, Fornara P, Lautenschlager C, Holzhausen HJ, Seliger B, Riemann satellites in acral melanoma in a Korean population. Ann Dermatol 25(1): D (2015) Immune signature of tumor infiltrating immune cells in renal 61–66. cancer. Oncoimmunology 4(1): e985082. Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, Xu M (2009) The Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, Wu C, Jiang J (2015) Prognostic prognostic value of peritumoral regulatory T cells and its correlation with role of tumor-infiltrating lymphocytes in lung cancer: a meta-analysis. Cell intratumoral cyclooxygenase-2 expression in clear cell renal cell Physiol Biochem 37(4): 1560–1571. carcinoma. BJU Int 103(3): 399–405. Grotz TE, Vaince F, Hieken TJ (2013) Tumor-infiltrating lymphocyte Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, Santarlasci V, response in cutaneous melanoma in the elderly predicts clinical outcomes. Serni S, Cosmi L, Maggi L, Angeli R, Mazzinghi B, Romagnani P, Maggi E, Melanoma Res 23(2): 132–137. Carini M, Romagnani S, Annunziato F (2011) Frequency of regulatory T 458 www.bjcancer.com | DOI:10.1038/bjc.2017.220 Prognostic role of immune cells in cancer BRITISH JOURNAL OF CANCER cells in peripheral blood and in tumour-infiltrating lymphocytes correlates Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, with poor prognosis in renal cell carcinoma. BJU Int 107(9): 1500–1506. Willard-Gallo K, Loi S (2015) The evaluation of tumor-infiltrating Man Y-G, Stojadinovic A, Mason J, Avital I, Bilchik A, Bruecher B, Protic M, lymphocytes (TILs) in breast cancer: recommendations by an Nissan A, Izadjoo M, Zhang X, Jewett A (2013) Tumor-infiltrating International TILs Working Group 2014. Ann Oncol 26(2): 259–271. immune cells promoting tumor invasion and metastasis: existing theories. Santoiemma PP, Powell Jr DJ (2015) Tumor infiltrating lymphocytes in J Cancer 4(1): 84–95. ovarian cancer. Cancer Biol Ther 16(6): 807–820. Mao Y, Qu Q, Chen X, Huang O, Wu J, Shen K (2016) The prognostic value Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating of tumor-infiltrating lymphocytes in breast cancer: a systematic review immunity’s roles in cancer suppression and promotion. Science 331: 1565–1570. and meta-analysis. PLoS ONE 11(4): e0152500. Shankaran V (2001) IFNg and lymphocytes prevent primary tumour Marvel D, Gabrilovich DI (2015) Myeloid-derived suppressor cells in the development and shape tumour immunogenicity. Nature 410: 1107–1111. tumor microenvironment: expect the unexpected. J Clin Invest 125(9): Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, Bajorin DF, 3356–3364. Reuter VE, Herr H, Old LJ, Sato E (2007) CD8 tumor-infiltrating Mei Z, Liu Y, Liu C, Cui A, Liang Z, Wang G, Peng H, Cui L, Li C (2014) lymphocytes are predictive of survival in muscle-invasive urothelial Tumour-infiltrating inflammation and prognosis in colorectal cancer: carcinoma. Proc Natl Acad Sci USA 104(10): 3967–3972. systematic review and meta-analysis. Br J Cancer 110(6): 1595–1605. Sideras K, Biermann K, Verheij J, Takkenberg BR, Mancham S, Hansen BE, Messaoudene M, Perier A, Fregni G, Neves E, Zitvogel L, Cremer I, Chanal J, Schutz HM, de Man RA, Sprengers D, Buschow SI, Verseput MC, Sastre-Garau X, Deschamps L, Marinho E, Larousserie F, Maubec E, Avril Boor PP, Pan Q, van Gulik TM, Terkivatan T, Ijzermans JN, Beuers UH, MF, Caignard A (2015) Characterization of the microenvironment in Sleijfer S, Bruno MJ, Kwekkeboom J (2017) PD-L1, Galectin-9 and CD8þ positive and negative sentinel lymph nodes from melanoma patients. PLoS tumor-infiltrating lymphocytes are associated with survival in One 10(7): e0133363. hepatocellular carcinoma. Oncoimmunology 6(2): e1273309. Mihm Jr. MC, Mule JJ (2015) Reflections on the histopathology of tumor- Sjodahl G, Lovgren K, Lauss M, Chebil G, Patschan O, Gudjonsson S, infiltrating lymphocytes in melanoma and the host immune response. Mansson W, Ferno M, Leandersson K, Lindgren D, Liedberg F, Cancer Immunol Res 3(8): 827–835. Hoglund M (2014) Infiltration of CD3(þ ) and CD68(þ ) cells in bladder Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer is subtype specific and affects the outcome of patients with muscle- cancer immunoediting and its three component phases—elimination, invasive tumors. Urol Oncol 32(6): 791–797. equilibrium and escape. Curr Opin Immunol 27: 16–25. Song H, Wu Y, Ren G, Guo W, Wang L (2015) Prognostic factors of oral Nguyen N, Bellile E, Thomas D, McHugh J, Rozek L, Virani S, Peterson L, mucosal melanoma: histopathological analysis in a retrospective cohort of Carey TE, Walline H, Moyer J, Spector M, Perim D, Prince M, McLean S, 82 cases. Histopathology 67(4): 548–556. Bradford CR, Taylor JM, Wolf GT (2016) Tumor infiltrating lymphocytes Stoll G, Bindea G, Mlecnik B, Galon J, Zitvogel L, Kroemer G (2015) and survival in patients with head and neck squamous cell carcinoma. Meta-analysis of organ-specific differences in the structure of the immune Head Neck 38(7): 1074–1084. infiltrate in major malignancies. Oncotarget 6(14): 11894–11909. Nordfors C, Grun N, Tertipis N, Ahrlund-Richter A, Haeggblom L, Sivars L, Sun DS, Zhao MQ, Xia M, Li L, Jiang YH (2012) The correlation between Du J, Nyberg T, Marklund L, Munck-Wikland E, Nasman A, Ramqvist T, tumor-infiltrating Foxp3þ regulatory T cells and cyclooxygenase-2 Dalianis T (2013) CD8þ and CD4þ tumour infiltrating lymphocytes in expression and their association with recurrence in resected head and neck relation to human papillomavirus status and clinical outcome in tonsillar cancers. Med Oncol 29(2): 707–713. and base of tongue squamous cell carcinoma. Eur J Cancer 49(11): Sun C, Xu J, Song J, Liu C, Wang J, Weng C, Sun H, Wei H, Xiao W, Sun R, 2522–2530. Tian Z (2015) The predictive value of centre tumour CD8(þ ) T cells in Obeid JM, Erdag G, Smolkin ME, Deacon DH, Patterson JW, Chen L, patients with hepatocellular carcinoma: comparison with Immunoscore. Bullock TN, Slingluff CL (2016) PD-L1, PD-L2 and PD-1 expression in Oncotarget 6(34): 35602–35615. metastatic melanoma: correlation with tumor-infiltrating immune cells Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, and clinical outcome. Oncoimmunology 5(11): e1235107. Gruber SB, Gallagher RP, Zanetti R, Rosso S, Dwyer T, Venn A, Ozgur HH, Ercetin AP, Eliyatkin N, Seren A, Kupelioglu A, Ortac R, Kanetsky PA, Groben PA, Hao H, Orlow I, Reiner AS, Luo L, Paine S, Diniz G, Aktas S (2014) Regulatory T cells and their prognostic value in Ollila DW, Wilcox H, Begg CB, Berwick M (2013) Tumor-infiltrating hepatopancreatobiliary tumours. Hepatogastroenterology 61(135): lymphocyte grade in primary melanomas is independently associated with 1847–1851. melanoma-specific survival in the population-based genes, environment Park CK, Kim SK (2017) Clinicopathological significance of intratumoral and and melanoma study. J Clin Oncol 31(33): 4252–4259. peritumoral lymphocytes and lymphocyte score based on the histologic Tu J-F, Ding Y-H, Ying X-H, Wu F-Z, Zhou X-M, Zhang D-K, Zou H, Ji J-S subtypes of cutaneous melanoma. Oncotarget 8(9): 14759–14769. (2016) Regulatory T cells, especially ICOSþ FOXP3þ regulatory T cells, Park JH, Roxburgh CS, McMillan DC (2014) Comment on ‘Tumour- are increased in the hepatocellular carcinoma microenvironment and infiltrating inflammation and prognosis in colorectal cancer: systematic predict reduced survival. Sci Rep 6: 35056. review and meta-analysis’. Br J Cancer 111(12): 2372. Ugel S, De Sanctis F, Mandruzzato S, Bronte V (2015) Tumor-induced Partlova S, Boucek J, Kloudova K, Lukesova E, Zabrodsky M, Grega M, myeloid deviation: when myeloid-derived suppressor cells meet tumor- Fucikova J, Truxova I, Tachezy R, Spisek R, Fialova A (2015) Distinct associated macrophages. J Clin Invest 125(9): 3365–3376. patterns of intratumoral immune cell infiltrates in patients with Wang B, Wu S, Zeng H, Liu Z, Dong W, He W, Chen X, Dong X, Zheng L, HPV-associated compared to non-virally induced head and neck Lin T, Huang J (2015) CD103þ tumor infiltrating lymphocytes predict a squamous cell carcinoma. Oncoimmunology 4(1): e965570. favorable prognosis in urothelial cell carcinoma of the bladder. J Urol Pretscher D, Distel LV, Grabenbauer GG, Wittlinger M, Buettner M, 194(2): 556–562. Niedobitek G (2009) Distribution of immune cells in head and neck Wang Q, Luan W, Warren L, Fiel MI, Blank S, Kadri H, Mandeli J, Hiotis SP cancer: CD8þ T-cells and CD20þ B-cells in metastatic lymph nodes are (2016) Prognostic role of immune cells in hepatitis B-associated associated with favourable outcome in patients with oro- and hepatocellular carcinoma following surgical resection depends on their hypopharyngeal carcinoma. BMC Cancer 9: 292. localization and tumor size. J Immunother 39(1): 36–44. Punt S, Dronkers EA, Welters MJ, Goedemans R, Koljenovic S, Bloemena E, Wansom D, Light E, Thomas D, Worden F, Prince M, Urba S, Chepeha D, Snijders PJ, Gorter A, van der Burg SH, Baatenburg de Jong RJ, Jordanova Kumar B, Cordell K, Eisbruch A, Taylor J, Moyer J, Bradford C, D’Silva N, ES (2016) A beneficial tumor microenvironment in oropharyngeal Carey T, McHugh J, Wolf G (2012) Infiltrating lymphocytes and human squamous cell carcinoma is characterized by a high T cell and low papillomavirus-16—associated oropharyngeal cancer. Laryngoscope IL-17(þ ) cell frequency. Cancer Immunol Immunother 65(4): 393–403. 122(1): 121–127. Saldanha G, Flatman K, Teo KW, Bamford M (2017) A novel numerical Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, Suchak K, scoring system for melanoma tumor-infiltrating lymphocytes has better Webb A, Hampton C, Patel NN, Randall CJ, Cox HJ, Jogai S, Primrose J, prognostic value than standard scoring. Am J Surg Pathol 41(7): 906–914. Piper K, Ottensmeier CH, King EV, Thomas GJ (2014) Tumour- Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, infiltrating lymphocytes predict for outcome in HPV-positive Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, oropharyngeal cancer. Br J Cancer 110(2): 489–500. Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Weiss SA, Han SW, Lui K, Tchack J, Shapiro R, Berman R, Zhong J, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Krogsgaard M, Osman I, Darvishian F (2016) Immunologic heterogeneity www.bjcancer.com | DOI:10.1038/bjc.2017.220 459 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer of tumor-infiltrating lymphocyte composition in primary melanoma. Hum non-muscle-invasive bladder cancer. Int J Clin Exp Pathol 8(9): 11510– Pathol 57: 116–125. 11516. Zhao HQ, Li WM, Lu ZQ, Yao YM (2014) Roles of Tregs in development of Wolf GT, Chepeha DB, Bellile E, Nguyen A, Thomas D, McHugh J (2015) hepatocellular carcinoma: a meta-analysis. World J Gastroenterol 20(24): Tumor infiltrating lymphocytes (TIL) and prognosis in oral cavity 7971–7978. squamous carcinoma: a preliminary study. Oral Oncol 51(1): 90–95. Xu Q, Wang C, Yuan X, Feng Z, Han Z (2017) Prognostic value of tumor- This work is licensed under the Creative Commons infiltrating lymphocytes for patients with head and neck squamous cell carcinoma. Transl Oncol 10(1): 10–16. Attribution-Non-Commercial-Share Alike 4.0 Inter- Zhang L (2003) Intratumoral T cells, recurrence, and survival in epithelial national License. To view a copy of this license, visit http:// ovarian cancer. N Engl J Med 348: 203–213. creativecommons.org/licenses/by-nc-sa/4.0/ Zhang Q, Hao C, Cheng G, Wang L, Wang X, Li C, Qiu J, Ding K (2015) High CD4(þ ) T cell density is associated with poor prognosis in patients with r The Author(s) named above 2017 460 www.bjcancer.com | DOI:10.1038/bjc.2017.220 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

British Journal of Cancer , Volume 117 (4) – Jul 13, 2017

Loading next page...
 
/lp/springer-journals/hype-or-hope-the-prognostic-value-of-infiltrating-immune-cells-in-30GCrcpCTP

References (94)

Publisher
Springer Journals
Copyright
Copyright © 2017 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
eISSN
1532-1827
DOI
10.1038/bjc.2017.220
Publisher site
See Article on Publisher Site

Abstract

MINIREVIEW British Journal of Cancer (2017) 117, 451–460 | doi: 10.1038/bjc.2017.220 Keywords: immune cells; tumour microenvironment; prognostic markers; cancer HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer 1 ,1 Tristan A Barnes and Eitan Amir Department of Medical Oncology and Hematology, Princess Margaret Cancer, Toronto, ON M5G 2M9, Canada Interactions between immune and malignant cells have been known to have clinical relevance for decades. The potential for immune control is now being therapeutically enhanced with checkpoint inhibitors and other novel agents to improve outcomes in cancer. The importance of the immune infiltrate as a prognostic marker is increasingly relevant. In this minireview, we present an overview of the immune infiltrate and its spatial organisation, and summarise the prognostic value of immune cells in different cancer types. International collaborative efforts are standardising histopathologic reporting of the immune infiltrate, to allow application of these parameters in the clinical and research settings. In general terms, a ‘pro-inflammatory’ tumour microenvironment and infiltrating CD8-expressing T lymphocytes are associated with improved clinical outcomes in a broad range of tumour types. The inhibitory function of other immune cells, for example, myeloid-derived suppressor cells and regulatory T cells, appear to have a major role in disrupting the capacity for the immune control of cancers. The immune system and malignant cells interact via a complex immune cells is also now recognised as contributing to the complex network. The importance of immune function in tumour immune response in cancer, some of which promote tumour development and control has been acknowledged for decades. As control and others facilitate cancer progression (Table 1; Figure 1). immunotherapy enters clinical practice, these underpinnings have more relevance as we try to identify predictive biomarkers for benefit from new therapies. The seminal papers describing the LOCATION AND SPATIAL ORGANISATION OF THE ‘hallmarks of cancer’ pronounced the capacity to avoid immune IMMUNE CELL INFILTRATE destruction as one of the requirements for malignancy (Hanahan and Weinberg, 2011). There is now a vast literature supporting Although the distinction between peritumoural, stromal and immunosurveillance as a significant contributor to the natural intratumoural lymphocytes is made histopathologically (Table 2), history of malignancy. The interaction between tumours and the this is likely an artificial segregation as this is a dynamic network that immune system has been described in three scenarios of allows chemokine-generated cell movement between these areas. ‘immunoediting’ (Schreiber et al, 2011); specifically: elimination A qualitative description of the interplay between tumour and (where immune surveillance successfully eradicates malignant immune cell infiltrate has been termed the ‘immune contexture’, cells); equilibrium (where the immune system exerts control over and includes the location of specific immune cells, tertiary abnormal cells) and escape (where tumour cells evade immune lymphoid structures (ectopic lymphoid aggregates that are mechanisms allowing growth and metastasis) (Mittal et al, 2014). generated during immune stimulation and exhibit structural In this mini-review, we aim to define the immune infiltrate and its characteristics of lymphoid organs), and the chemokines and spatial organisation as well as summarising the prognostic value of cytokines involved in this microenvironmental organisation immune cells in different solid cancers. (Fridman et al, 2011). Methods for describing the immune infiltrate are a limitation of current pathological reporting. There remains a lack of consensus regarding reporting of tumour- SUBTYPES OF IMMUNE CELL INFILTRATE infiltrating lymphocytes (TILs), including methods to subtype the infiltrating cells and their spatial organisation. International Historically, studies have focused on the interaction between working groups are trying to create and validate reporting cytotoxic T lymphocytes and cancer cells. The role of other guidelines (Salgado et al, 2015). Immunophenotyping of the *Correspondence: Dr E Amir; E-mail: eitan.amir@uhn.ca Received 15 December 2016; revised 25 May 2017; accepted 1 June 2017; published online 13 July 2017 r The Author(s) named above Published by Springer Nature on behalf of Cancer Research UK. 451 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer Table 1. Cell types in the tumour immune infiltrate Expression Function Lymphoid Cytotoxic T lymphocyte CD3, CD8 Recognise and lyse target cells through release of perforin and granzymes. Activated by dendritic cell antigen presentation via major histocompatibility complex (MHC) Class I antigen to T cell receptor. Apoptosis is induced in cells expressing specific antigen Regulatory T lymphocyte (also CD3, CD4, Serve to maintain tolerant to self antigens; inhibit dendritic cell function of antigen presentation and thus called suppressor T cells) CD25, FOXP3 inhibits both the expansion and the differentiation of T effector cells. Polyclonal Tregs appear to modulate differentiation and cell trafficking T helper lymphocyte (Th cell) CD4 Help to modulate immune responses. Activate and promote growth of cytotoxic T cells; maximise activity of phagocytes through interaction with MHC Class II; role in B cell antibody class switching (e.g., from immunoglobulin-M to immunoglobulin-G) Natural killer cell (NK) CD16, CD56 A subset of cytotoxic lymphocytes that can be activated in the absence of MHC Class I antigen presentation, thus an important component of the innate immune system Myeloid Dendritic cells CD40 Act to process and present antigen on MHC Class I, and via co-stimulatory molecules they serve to activate T lymphocytes Myeloid-derived suppressor cells CD11b, CD66b Pathologically activated immature myeloid cells, with morphological and phenotypical similarity to (MDSC) mononuclear and polymorphonuclear cells. Prevent activation of T cells and have a role in promoting tumour growth and metastasis Macrophages CD68 Part of the innate immune defence with phagocytic capacity, and also have a role in adaptive immunity through activation of other immune cells via cytokine release. M1 macrophages are pro-inflammatory (largely driven by interferon (IFN)-gamma); M2 macrophages release anti-inflammatory cytokines such as IL4, IL10, TGF-beta and nuture tolerance Activating Inhibitory CD4 helper cell (Th1 cell) CD40 CD8 IL2 + + CD25 , FOXP3 OX40 Regulatory T lymphocyte IFNγ ADO receptor IL4 TIM3 IL10 Inhibitory + – + IFNγ TGFβ cytokines CD8 cytotoxic TNFα LAG3 CD28 T lymphocyte + CTLA4 CD40 CD80 PD1 PD1/PDL1 Tumour B7 Myeloid-derived antigen Dendritic cell suppressor cell Tumour cell Figure 1. Pathways affecting cytotoxic T lymphocyte activity within the tumour microenvironment. Table 2. Location of the immune infiltrate Infiltrate Location Intratumoural Within the mass (or nest) of malignant cells, with direct proximity between cancer and immune cells Stromal In the surrounding connective tissues and blood vessels Peritumoural Around the tumour and can refer to cells at the advancing margin of the tumour, in the stroma or the tissues adjacent to the tumour immune infiltrate by immunohistochemistry or immunofluores- of immune co-regulated genes may help to identify and cence staining can be performed in tissue samples, or after characterise the immune infiltrate (Stoll et al, 2015). Meta- generation of cell suspensions that are generated by mechanical or analytical data suggest that in most cancers, the immune infiltrate enzymatic breakdown of fresh tumour tissue (Stoll et al, 2015). The is heterogeneous and there is limited reproducibility of leukocyte use of sectioned tissue specimens allows spatial understanding of subtypes (Stoll et al, 2015). Although the presence of T cells is cell position relative to tumour cells, however, similar to the use of clearly important, the interplay between tumour antigens and cell suspension, is limited by challenges in antigen retrieval major histocompatibility complex (MHC) molecules for antigen (capacity to bind identifying/specific proteins of interest) and poor presentation is critical for efficient T cell activation. High affinity of standardisation. Novel approaches such as mRNA characterisation the targeted peptides for MHC is required for strong stimulation of 452 www.bjcancer.com | DOI:10.1038/bjc.2017.220 Prognostic role of immune cells in cancer BRITISH JOURNAL OF CANCER T cells to secrete cytokines and produce tumour eradication or only appear to translate into improved longer term outcomes in control (Engels et al, 2013). The specific antigenicity of coding non-luminal tumours. exons in mutated cancer genes is an area of research and the A meta-analysis of 25 published studies comprising over 22 000 capacity to sequence whole genomes with greater speed and patients, failed to show that immune infiltrates are associated with reduced cost is enhancing the capacity to identify potentially overall survival (OS) in unselected breast cancer patients, but did antigenic mutations. find such an association in TNBC (hazard ratio (HR): 0.79; 95% confidence interval (CI): 0.71–0.87). CD8-expressing lymphocytes were associated with improved disease-free survival (DFS; HR: 0.69; 95% CI: 0.56–0.84) and breast cancer-specific survival (HR: PROGNOSTIC VALUE OF INFILTRATING IMMUNE CELLS 0.78; 95% CI: 0.71–0.86) in the overall population, whereas the FOXP3-expressing lymphocytes were associated with worse DFS The prognostic value of lymphocytes in stromal, peritumoural and (HR: 1.47; 95% CI: 1.06–2.05) and OS (HR: 1.50; 95% CI: intratumoural locations remains unclear, with conflicting data from 1.15–1.97, P¼ 0.004) (Mao et al, 2016). different tumour sites. Peritumoural lymphocytes at the advancing Clinical trials have not reported an association between TIL, tumour margin and those in direct contact with tumour cells have nuclear grade or histopathological grade in TNBC with most been purported to carry the most prognostic weight particularly in making the assumption that TNBC are high grade (Adams et al, some disease sites (see below). In general terms, a ‘pro-inflamma- 2014). It remains uncertain whether this association may be tory’ tumour microenvironment and infiltrating CD8-expressing T explained partly by response to chemotherapy; lower grade luminal lymphocytes are associated with improved clinical outcomes in a tumours have lesser response to cytotoxic therapy and are less broad range of tumour types. In contrast, the inhibitory function of frequently associated with infiltrating immune cells. other immune cells, for example, myeloid-derived suppressor cells A Th1 immune phenotype and mRNA profiles consistent with and regulatory T cells (Tregs) appear to have a major role in immune activation have also been associated with response to disrupting the capacity for the immune control of cancers and are neoadjuvant chemotherapy (Denkert et al, 2015). There is more therefore associated with worse outcome. variability in results seen in trials reporting outcome for CD4- Perhaps counter-intuitively, favourable outcomes have also been expressing T lymphocytes and FOXP3-expressing Tregs. The observed in tumours infiltrated by inhibitory immune cells, for presence of Tregs prior to chemotherapy is associated with higher example, forkhead box P3-positive regulatory T cells (FOXP3) cells probability of attaining a pathological complete response (pCR), in colorectal cancer. This may represent a feedback loop in the which probably reflects their association with a higher number of context of an existing anti-tumour immune response and thus CD8-expressing cells. A high ratio of CD8:FOXP3 cells and a lower actually indicate increased tumour immunogenicity (Gajewski proportion of FOXP3 at the end of neoadjuvant chemotherapy may et al, 2013). Myeloid-derived suppressor cells (MDSC) and have a more meaningful prognostic value (Dushyanthen et al, 2015). tumour-associated macrophages are both capable of negative The current working group have recommended semi-quantita- regulation of innate and adaptive immune pathways. MDSCs have tive assessment of stromal TILs and at this stage do not advocate a role in tumour growth and metastasis via promotion of immune for sub-classification of lymphocytes (Salgado et al, 2015). This is privilege (ability to tolerate the introduction of antigens without due to both the greater reproducibility of stromal TIL measure- eliciting an inflammatory immune response), tumour microenvir- ment compared with intratumoural TILs, which are difficult to onment remodelling, establishment of a pre-metastatic niche distinguish from malignant cells in standard H&E sections, and the (a scenario where non-cancer cells promote future metastasis) fact that in TNBC and HER2-positive breast cancer, the prognostic and interaction with tumour to promote differentiation, invasion power of TILs persists among all subtypes of infiltrating immune and angiogenesis (Marvel and Gabrilovich, 2015). There is cells (Salgado et al, 2015). evidence that MDSC expansion is associated with more advanced stages of malignancy in multiple cancer types and also correlates Colorectal cancer. Several scoring systems have been proposed for with poor prognosis independent of tumour burden (Ugel et al, quantifying the inflammatory response in colorectal cancer. These 2015). Paradoxically, anti-tumour immunity also leads to selective include the Jass score, the Immunoscore and the Klintrup–Ma¨kinen pressure on malignant cells, which ultimately leads to survival of grade of overall peritumoural inflammation (Park et al, 2014). There tumour cells with reduced immunogenicity (Shankaran, 2001). is evidence that TILs are associated with greater prognostic value There are also data supporting the hypothesis that tumour- than the American Joint Committee on Cancer TNM stage (Jochems infiltrating immune cells can promote invasion and metastases and Schlom, 2011). In a meta-analysis of nine trials examining (Man et al, 2013), which may in part explain the heterogeneity of tumour inflammation in colorectal cancer, the pooled HR confirmed results between studies examining this topic. an OS benefit for patients with prominent TILs compared with those without, with a HR of 0.59 (95% CI: 0.48–0.72, Po0.001) and a HR for cancer-specific survival of 0.40 (95% CI: 0.27–0.61, Po0.001). TUMOUR-SPECIFIC PROGNOSTIC VALUE There were differences between all the studies in the thresholds used to determine TIL positivity of tumours, for example, some used Breast cancer. In breast cancer, the presence of TILs is associated mean or median cut offs, others used high vs low scores of Klintrup– with improved prognosis in human epidermal growth factor Makinen or Jass scores (Mei et al, 2014). The evaluation of T cell receptor 2 (HER2) positive and triple negative breast cancers subsets and specific location of lymphocytic infiltrate did not show (TNBC), but not in luminal subtypes. In addition, the recognition strong prognostic value, specifically CD3, CD8, FOXP3 and at of the prognostic value of the immune infiltrate has been the basis different sites (tumour centre, peritumoural stroma and invasive for establishing a breast cancer immunological grade (Salgado et al, tumour margin) were examined. CD3-positive cells at the invasive 2015). margin had OR for DFS of 0.4 (95% CI: 0.35–0.68) and for OS of Independent of other clinicopathological prognostic factors or 0.63 (95% CI: 0.42–0.93). This analysis was limited by significant chemotherapy regimens, multiple studies have confirmed stromal inter-study heterogeneity (Mei et al, 2014). This contrasts to earlier TILs are associated with higher rates of pathological complete individual study data showing statistically significant association response (pCR) to neoadjuvant chemotherapy in all subgroups between the type of immune cell density at the centre of the tumour evaluated (including ER positive, HER2-positive tumours) or the infiltrating margin and patient outcome (Jochems and (Dushyanthen et al, 2015). However, these differences in response Schlom, 2011). www.bjcancer.com | DOI:10.1038/bjc.2017.220 453 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer Ovarian cancer. In a meta-analysis of 10 studies comprising 1815 infiltrating cells may not be as important as the proportion of patients with treated ovarian carcinoma (Hwang et al, 2012), presence CD8-expressing cells relative to all infiltrating cells. The prognostic of intra-epithelial T lymphocytes was associated with improved OS value of intratumoural CD8-positive lymphocytes appears superior (pooled HR for death 0.45, 95% CI: 0.34–0.58, Po0.001). CD3- and even to the adequacy of surgical debulking in prognosticating for CD8-expressing lymphocytes were both examined, and both both progression free survival and OS (Zhang, 2003). conferred a survival advantage; CD8 was examined more frequently and demonstrated a larger magnitude of effect on OS than CD3 Non-small cell lung cancer. In a meta-analysis of 29 trials with (pooled HR: 0.46 and 0.57, respectively) (Hwang et al, 2012). over 86 000 patients, high levels of CD8-expressing cells infiltrating This positive association between CD8-expressing lymphocytes the tumour or in the tumour stroma of non-small cell lung cancer and clinical outcome is also observed in the assessment of patients (NSCLC) specimens were associated with better OS (HR: 0.76 and before treatment and following neoadjuvant chemotherapy. Data 0.80, respectively) compared with tumours without lymphocytes on CD3-expressing lymphocytes, B cells and NK cells are less clear present. CD3 expression also demonstrated similar findings; (Santoiemma and Powell, 2015). There are conflicting data pooled HR for OS 0.65 (95% CI: 0.50–0.84, P¼ 0.001) for stromal regarding FOXP3-positive Tregs, with a few studies demonstrating CD3 cells and 0.66 (95% CI: 0.45–0.97, P¼ 0.03) for intratumoural superior outcome, but most studies suggesting a negative impact CD3 cells. Presence of intratumoural CD4-expressing cells between on survival outcomes through inhibition of cytotoxic T cell activity the tumour cells resulted in improved OS (HR: 0.65; 95% CI: 0.46– (Santoiemma and Powell, 2015). The measured absolute number of 0.91, P¼ 0.01). Despite a higher effect size, a significant association Table 3. Studies examining the prognostic impact of infiltrating immune cells in melanoma Study Number Result Association Cell type (Kakavand 60 Positive correlation between CD3, CD4 and CD8 cells in sentinel node and DFS/OS; Positive CD3, CD4 and et al, 2015) PD1þ lymphocytes associated with worse outcome association CD8 (Saldanha et al, 655 Higher TILs are associated with better prognosis; confirms value of a simplified numerical Positive TIL 2017) TIL scoring system association (Park and Kim, 177 Density of lymphocytes in the peritumoural and intratumoural regions were both Positive TIL 2017) prognostic association (Obeid et al, 147 Expression of PD-L1 and PD-L2 correlated with increasing densities of immune cells. PD-L2 Positive PD-L2 and TILs 2016) expression associated with improved OS association (Weiss et al, 1241 Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile Positive TILs 2016) and improved prognosis compared with melanomas with non-brisk or absent TILs association (Garg et al, 57 B cells are associated with a significantly better overall survival in patients with cutaneous Positive B cells 2016) primary melanomas of 41 mm Breslow depth association (Bosisio et al, 710 Sheets/clusters of plasma cells associated with worse prognosis than melanomas without Negative Plasma cells 2016) plasma cells association (Messaoudene 39 NK cells in SLN associated with higher risk of relapse; NK cells did not correlate with Negative NK cells et al, 2015) thickness of primary but with patient age association (Fortes et al, 4133 High levels TILs associated with improved OS Positive TIL 2015) association (Song et al, 82 TILs decreased the risk of distant metastases in oral mucosal melanoma Positive TIL 2015) association (Donizy et al, 104 High levels TILs associated with improved OS Positive TIL 2015) association (Eriksson et al, 4237 TILs demonstrated no prognostic value for survival No TIL 2015) association (Thomas et al, 3330 High levels TILs associated with improved OS Positive TIL 2013) association (Cintolo et al, 161 Absence of TIL was associated with worse DSS; In radial growth phase presence of TIL with Positive TIL 2013) regression was associated with a poor prognosis association (Lee et al, 90 Brisk TILs were associated with improved prognosis in acral melanoma Positive TIL 2013) association (Grotz et al, 250 TILs in elderly melanoma patients predicts both SLN metastasis and improved melanoma- Positive TIL 2013) specific outcomes association (Azimi et al, 1865 TIL grade is an independent predictor of OS. Pronounced TIL infiltrate associated with Positive TIL 2012) excellent prognosis association (Erdag et al, 147 Higher densities of CD8þ T cells correlated best with survival, a higher density of CD45þ Positive CD8, CD45, T 2012) leukocytes, T cells, and B cells also correlated with increased survival association cells and B cells (Ladanyi et al, 106 CD20þ B cells most often found in peritumoural stroma, correlated with activated T Positive CD20 B cells and 2011) lymphocytes and high number of these cells provided OS advantage association activated T cells (Knol et al, 102 High Foxp3 expression using qPCR predicts for worse progression free survival in stage III Negative FOXP3 2011) melanoma patients association (Burton et al, 515 TIL response is a significant predictor of SLN metastasis but is not a major predictor of DFS No TIL 2011) or OS association Abbreviations: DFS¼ disease-free survival; DSS¼ disease specific survival; NK¼ natural killer; OS¼ overall survival; SLN¼ sentinal lymph node; TIL¼ tumour-infiltrating lymphocytes. 454 www.bjcancer.com | DOI:10.1038/bjc.2017.220 Prognostic role of immune cells in cancer BRITISH JOURNAL OF CANCER Table 4. Immune cells in renal cell carcinoma Number Study Result Association Cell type patients (Geissler 104 Tumour-infiltrating NK cells and Th1 markers associated with increased OS, for example, Positive association; NK and Th1; T et al, 2015) HLA-DRC and CXCR3C T cells; whereas a high number of T cells, especially with high negative association cells (CD69) CD69 expression correlated with worse prognosis (Kang et al, 199 PD1-positive or FoxP3-positive lymphocytes predicted poor OS survival Negative association FOXP3, 2013) PD1þ lymphocytes (Hotta 105 Low levels of memory T cells had improved OS Negative association Memory T et al, 2015) cells (Eckl et al, 41 NK cell percentage does not provide prognostic information No association NK cells 2012) (Liotta 30 Increase in both peripheral and intratumoural Tregs associated with worse prognosis Negative association Tregs et al, 2011) (Li et al, 125 Increased peritumoural Tregs are associated with worse prognosis in clear cell renal cell Negative association Tregs 2009) carcinoma (Bromwich 73 Increased CD4þ T cells associated with worse cancer-specific survival; no association Negative association CD4 et al, 2003) demonstrated with CD8þ T cells Abbreviations: NK¼ natural killer; OS¼ overall survival. Table 5. Studies of TILs in head and neck squamous cell carcinoma Number Study Result Association Cell type patients (Xu et al, 202 TIL level was an independent positive prognostic factor for DFS Positive TIL 2017) association (Kogashiwa 84 PD-L1 expression was associated with CD8þ tumour-infiltrating lymphocytes and Positive CD8 et al, 2017) better outcome in patients with locally advanced oropharyngeal SCC association (Punt et al, 162 High number of T cells was correlated with improved DFS in HPV-positive Positive T cells, Th17 2016) oropharyngeal SCC; improved outcome correlated with active Th17 cells and lower association IL-17(þ ) non-T cells (Nguyen 278 Higher CD4 levels predicted improved OS and disease-specific survival Positive CD4 et al, 2016) association (Caldeira 28 Increased neutrophilic infiltration demonstrated in tumours with higher T stage; no No association Neutrophils et al, 2015) correlation with survival (Balermpas 161 CD8þ TILs constitute an independent prognostic marker in HNSCC patients treated Positive CD8 et al, with adjuvant chemoradiotherapy; prognostic benefit is apparent in HPV pos and neg association 2016b) subgroups (Partlova 54 HPV-positive tumour showed significantly higher numbers of infiltrating IFNgþ Positive IFNgþ CD8þ T et al, 2015) CD8þ T lymphocytes, IL-17þ CD8þ T lymphocytes, myeloid dendritic cells and are association cells, IL-17 CD8þ T associated with better outcome compared to HPV-negative cells (Wolf et al, 39 CD68þ macrophages were found associated with positive nodes and poorer overall Negative Macrophages 2015) survival (not significant) association (Ward et al, 270 TIL levels prognostic in HPV-positive HNSCC Positive TIL 2014) association (Balermpas 101 High infiltrating CD3þ and CD8þ cells correlate with survival outcomes with Positive CD3þ and CD8þ T et al, 2014) chemoradiation association cells (Nordfors 203 Higher CD8(þ ) TIL counts correlated to a better 3-year OS in HPV pos; no correlation Positive CD8; CD4 et al, 2013) of CD4(þ ) TILs with survival outcomes association; no association (Fraga et al, 70 CD57þ TILs do not correlate with survival outcomes No association CD57 2012) (Wansom 46 T-cell infiltration did not differ by HPV status; related to DSS and OS; after adjusting Positive CD8, FOXP3 and et al, 2012) for HPV status, CD8, FoxP3, and total T cells were significantly associated with DSS association total T cells and OS (Sun et al, 83 Tumour-infiltrating CD4þ CD25(high) Foxp3þ Tregs correlated with intratumoural No association FOXP3 2012) COX-2 expression and were associated with a worse recurrence free survival in univariate but not multivariate analysis (Pretscher 33 Intra-epithelial CD8 cells in metastatic lymph nodes and high CD20þ Bcells in Positive CD8, B cells et al, 2009) lymphoid tissue of lymph node metastases were associated with improved DFS association (Badoual, 84 CD4þ CD69þ T cells are associated with improved OS Positive CD4CD69þ T cells 2006) association Abbreviations: DFS¼ disease-free survival; DSS = disease specific survival; HNSCC = head and neck SCC; OS¼ overall survival; SCC¼ squamous cell carcinoma; TIL¼ tumour-infiltrating lymphocytes. www.bjcancer.com | DOI:10.1038/bjc.2017.220 455 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer between stromal CD4-expressing cells and outcome was not Urothelial cancers. The approval of immunotherapy in the observed (HR 0.43; 95% CI: 0.07–2.61, P¼ 0.36), likely due to treatment of advanced urothelial malignancy suggests the relevance greater heterogeneity. FOXP3-expressing T cells in the tumour of the immune system. This is supported by most studies stroma had association with worse progression-free and OS (HR: demonstrating the positive prognostic value of CD3, CD4 and 2.14; 95% CI: 1.68–2.72; Po0.001) and 2.67 (95% CI: 1.74–4.08; CD8 T cells, and the negative association of FOXP3-positive T cells Po0.001, respectively) (Geng et al, 2015). with survival, see Table 6. Melanoma. Checkpoint inhibitors were first approved in mela- Hepatocellular carcinoma. Several studies have examined the noma after a long history of interest in the immune response to role of the intratumoural and peritumoural (parenchymal) these tumours after observation of spontaneous responses (Mihm infiltrate in hepatocellular carcinoma (HCC) (Table 7). High and Mule, 2015). One histopathological definition of the immune levels of FOXP3 Tregs are associated with worse DFS and OS. response in melanoma categorised the immune infiltrating response Two large meta-analyses performed in 2014 demonstrate the as ‘brisk’, a scenario where lymphocytes are demonstrated in the importance of FOXP3 in both the development and prognosis of entire tumour mass or along the advancing edge; ‘non-brisk’, where HCC (Huang et al, 2014; Zhao et al, 2014). Gabrielson et al, 2016 lymphocytes are seen focally in the centre of the tumour or along applied the Galon Immunoscore (Galon et al, 2014) to HCC and part of the invasive margin; or ‘absent’ with no tumoural confirmed its prognostic value, CD3 and CD8 cell densities lymphocytes at all or lymphocytes seen, but not interacting with predicted recurrence with ORs of 5.8 (95% CI: 1.6–21.8) and 3.9 melanoma cells. These subgroups provide prognostic information in (95% CI: 1.1–14.2), respectively. PDL1 staining was positively historical studies. In one study, melanoma-specific death was 30 and correlated with high CD3 and CD8 density and predicted a lower 50% lower in the non-brisk and brisk groups, respectively, compared rate of recurrence (Gabrielson et al, 2016). The applicability of with the absent group (Mihm and Mule, 2015). In contrast, studies these tools remains limited by routine access to technology to report no survival advantage with lymphocytic infiltrate particularly subtype these T cells. with respect to tumours of earlier stage and not in the radial growth Other tumour types. The prognostic role of the immune infiltrate phase (Ladanyi, 2015). However, overall, there is a large body of evidence documenting the prognostic value of the immune infiltrate in less common malignancies is summarised in the Online Appendix. in melanoma (see summary in Table 3). Renal cell carcinoma. There is contradictory evidence regarding the role of the immune cell infiltrate in renal cell carcinoma. BRAIN METASTASES Multiple studies have demonstrated a worse outcome in patients with a neutrophilic, and/or lymphocytic infiltrate (Jochems and Although the central nervous system (CNS) has been purported to Schlom, 2011), a finding which appears reproducible (Table 4). be an ‘immune privileged’ site, there is an increasing evidence The reasons for this are not clear. supporting the role of immune infiltrating cells in brain tumours. In Head and neck cancer. Several clinical trials have demonstrated a study by Harter et al, TILs in brain metastases from different that tumour infiltration by CD3- and CD8-expressing T cells tumour types were quantified and associated with outcome. This was correlates with improved disease outcome in chemoradiother- then validated in a breast cancer only brain metastases cohort. apy-treated patients with head and neck cancer. This positive Carcinomas demonstrated more frequent stromal infiltration, prognosis holds true regardless of the human papilloma virus whereas TILs in melanoma were more often diffusely infiltrative. (HPV) DNA status (Balermpas et al, 2016a). Smoking-associated High TILs level, high-programed cell death protein (PD)1þ /CD8þ tumours with higher degrees of genomic instability and higher and programed death ligand (PDL)-1 staining were associated with antigenicity would be expected to have increased potential to smaller tumours but there was no significant association with activate an immune response; however, this is not supported by survival demonstrated (Harter et al, 2015). In contrast, Bienkowski clinical evidence. There is conflicting information regarding and Preusser, 2015 provide a review of the literature in which they differences in the immune infiltrate in HPV-positive vs negative concluded that tumour-infiltrating lymphocyte density in CNS status (Wansom et al, 2012; Partlova et al, 2015); see Table 5. metastases were strongly associated with improved OS . Table 6. Studies examining prognostic impact of immune cells in bladder cancer Number Study Result Association Cell type patients (Krpina et al, 115 CD3þ and CD8þ TIL are predictive of bladder cancer recurrence in patients with Positive association CD3 and CD8 2015) solitary low-grade non-muscle invasive bladder cancer (Wang et al, 302 Intratumoural CD103(þ ) TILs inversely associated with tumour size. High CD103þ cells Positive association CD103þ 2015) associated with improved OS. (Zhang et al, 131 Tumour-infiltrating CD4(þ ) T cell density emerged as an independent prognostic factor Positive association CD4 2015) for OS (HR: 2.75; P¼ 0.004) Knief et al 149 FOXP3/CD8 (OS: P¼ 0.013, HR: 1.32, 95% CIs: 1.06–1.65) ratios were significantly Negative association FOXP3/CD8 (2016) associated with briefer OS and time to cancer-specific death ratio (Sjodahl et al, 296 CD3(þ ) TILs was significantly associated with good prognosis. Positive association with Positive association; CD3þ ; High 2014) CD3 was modulated by CD68(þ ) TAMs. Strongest negative association with survival was Negative association CD68/CD3 ratio a high ratio between CD68 and CD3 (Sharma et al, 69 Higher numbers of CD8 TILs within the tumour (4 or ¼ 8) had better DFS and OS Positive association CD8 2007) (Hilmy et al, 103 No correlation between TIL level and prognosis No association TILs 2006) Abbreviations: TAM¼ tumour-associated macrophage; OS¼ overall survival; TIL¼ tumour-infiltrating lymphocytes. 456 www.bjcancer.com | DOI:10.1038/bjc.2017.220 Prognostic role of immune cells in cancer BRITISH JOURNAL OF CANCER Table 7. Studies examining prognostic value in HCC Number Study Result Association Cell type patients (Sideras 154 Low CD8þ TIL associated with poor HCC-specific survival. Positive CD8 et al, 2017) association (Gabrielson 65 Intratumoural and peri-tumoural CD3þ /CD8þ density associated with lower risk of Positive CD3/CD8 ratio et al, 2016) recurrence association (Tu et al, 57 FOXP3þ Tregs/CD4þ T cells ratio was an independent prognostic factor for OS Positive FOXP3/CD4 ratio 2016) association (Wang et al, 66 Tumour CD4 and CD8 lower than non-neoplastic liver; high Foxp3 associated with poor Negative FOXP3 2016) OS, whereas low CD8 expression in non-neoplastic liver associated with high HCC association recurrence rate. (He et al, 149 High neutrophil to lymphocyte ratio in peritumoural tissues correlated with poor Negative Neutrophil:lymphocyte 2015) prognosis in patients with HCC association ratio (Sun et al, 449 CD8þ in tumour centre had highest prognostic impact on DFS and OS Positive CD8 2015) association (Ozgur et al, 8 High FoxP3þ poorer DFS Negative FOXP3 2014) association (Brunner 119 IL-33 and CD8þ cells associated with prolonged OS Positive IL-33 and CD8 et al, 2015) association (Huang 1964 OS significantly lower in high FOXP3 infiltrated tumours than low (at 1, 3 and 5 years) Positive FOXP3 et al, 2014) (meta-analysis 13 studies) association Abbreviations: HCC¼ hepatocellular carcinoma; OS¼ overall survival; TIL¼ tumour-infiltrating lymphocytes. Summary. Broadly speaking, the immune infiltrate can be Badoual C (2006) Prognostic value of tumor-infiltrating CD4þ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12: 465–472. classified as a ‘pro-inflammatory’ phenotype with infiltrating T Balermpas P, Michel Y, Wagenblast J, Seitz O, Weiss C, Rodel F, Rodel C, cells and a cytokine profile consistent with immune activation. Fokas E (2014) Tumour-infiltrating lymphocytes predict response to Immune control of tumours can occur spontaneously, and the definitive chemoradiotherapy in head and neck cancer. Br J Cancer 110(2): presence of an immune infiltrate is generally a good prognostic 501–509. sign. However, the immune infiltrate has variable effect in Balermpas P, Ro¨del F, Ro¨del C, Krause M, Linge A, Lohaus F, Baumann M, prognostic models depending on the tumour type, location of Tinhofer I, Budach V, Gkika E, Stuschke M, Avlar M, Grosu A-L, the cells and state of activation; the complexity of immune Abdollahi A, Debus J, Bayer C, Stangl S, Belka C, Pigorsch S, Multhoff G, networks are likely oversimplified in current measurement models. Combs SE, Monnich D, Zips D, Fokas E (2016a) CD8þ tumour- Tumour evasion through inhibitory mechanisms may serve as a infiltrating lymphocytes in relation to HPV status and clinical outcome in predictive marker for benefit from immunotherapy, which inhibits patients with head and neck cancer after postoperative negative regulators of the immune system. Alternatively, the chemoradiotherapy: a multicentre study of the German cancer consortium microenvironment may lack immune cell infiltration, and tumour radiation oncology group (DKTK-ROG). Int J Cancer 138(1): 171–181. resistance is likely through immune system ignorance (Gajewski Balermpas P, Rodel F, Rodel C, Krause M, Linge A, Lohaus F, Baumann M, Tinhofer I, Budach V, Gkika E, Stuschke M, Avlar M, Grosu AL, et al, 2013), and therefore promoting immune activation is less Abdollahi A, Debus J, Bayer C, Stangl S, Belka C, Pigorsch S, Multhoff G, likely to be successful in this setting. Combs SE, Monnich D, Zips D, Fokas E (2016b) CD8þ tumour- For tumour-infiltrating immune cells to live up to the ‘hype’ of infiltrating lymphocytes in relation to HPV status and clinical outcome in inducing and promoting long-term tumour control and contribute patients with head and neck cancer after postoperative as valuable prognostic markers, their subtype (especially activated chemoradiotherapy: a multicentre study of the German cancer consortium antigen specific cytotoxic T lymphocytes) and position (organised radiation oncology group (DKTK-ROG). Int J Cancer 138(1): 171–181. spatial response) need to be defined and measured in a standardised Bienkowski M, Preusser M (2015) Prognostic role of tumour-infiltrating manner. Successful inclusion of immune cell markers in prognostic inflammatory cells in brain tumours: literature review. Curr Opin Neurol clinical models is becoming a realistic hope in some cancers. 28(6): 647–658. Bosisio FM, Wilmott JS, Volders N, Mercier M, Wouters J, Stas M, Blokx WAM, Massi D, Thompson JF, Scolyer RA, van Baren N, van den Oord JJ CONFLICT OF INTEREST (2016) Plasma cells in primary melanoma. Prognostic significance and possible role of IgA. Mod Pathol 29(4): 347–358. Bromwich EJ, McArdle PA, Canna K, McMillan DC, McNicol A, Brown M, The authors declare no conflict of interest. Aitchison M (2003) The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer. Br J Cancer 89(10): 1906–1908. REFERENCES Brunner SM, Rubner C, Kesselring R, Martin M, Griesshammer E, Ruemmele P, Stempfl T, Teufel A, Schlitt HJ, Fichtner-Feigl S (2015) Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Tumor-infiltrating, interleukin-33-producing effector-memory CD8(þ ) Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, T cells in resected hepatocellular carcinoma prolong patient survival. Sledge GW, Sparano JA, Badve SS (2014) Prognostic value of tumor- Hepatology 61(6): 1957–1967. infiltrating lymphocytes in triple-negative breast cancers from two phase Burton AL, Roach BA, Mays MP, Chen AF, Ginter BA, Vierling AM, III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. Scoggins CR, Martin RC, Stromberg AJ, Hagendoorn L, McMasters KM J Clin Oncol 32(27): 2959–2966. (2011) Prognostic significance of tumor infiltrating lymphocytes in melanoma. Am Surg 77(2): 188–192. Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, Saw RP, Thompson JF (2012) Tumor-infiltrating lymphocyte grade is an Caldeira PC, de Andrade Sousa A, de Aguiar MC (2015) Differential independent predictor of sentinel lymph node status and survival in infiltration of neutrophils in T1-T2 versus T3-T4 oral squamous cell patients with cutaneous melanoma. J Clin Oncol 30(21): 2678–2683. carcinomas: a preliminary study. BMC Res Notes 8: 569. www.bjcancer.com | DOI:10.1038/bjc.2017.220 457 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer Cintolo JA, Gimotty P, Blair A, Guerry D, Elder DE, Hammond R, Elenitsas R, Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Xu X, Fraker D, Schuchter LM, Czerniecki BJ, Karakousis G (2013) Local Cell 144(5): 646–674. immune response predicts survival in patients with thick (t4) melanomas. Harter PN, Bernatz S, Scholz A, Zeiner PS, Zinke J, Kiyose M, Blasel S, Ann Surg Oncol 20(11): 3610–3617. Beschorner R, Senft C, Bender B, Ronellenfitsch MW, Wikman H, Denkert C, Gv Minckwitz, Brase JC, Sinn BV, Gade S, Kronenwett R, Glatzel M, Meinhardt M, Juratli TA, Steinbach JP, Plate KH, Wischhusen J, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Weide B, Mittelbronn M (2015) Distribution and prognostic relevance of Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, Andre F, tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune Klauschen F, Blohmer J-U, Krappmann K, Schmidt M, Tesch H, checkpoints in human brain metastases. Oncotarget 6(38): 40836–40849. Ku¨mmel S, Sinn P, Jackisch C, Dietel M, Reimer T, Untch M, Loibl S He G, Zhang H, Zhou J, Wang B, Chen Y, Kong Y, Xie X, Wang X, Fei R, (2015) Tumor-infiltrating lymphocytes and response to neoadjuvant Wei L, Chen H, Zeng H (2015) Peritumoural neutrophils negatively chemotherapy with or without carboplatin in human epidermal growth regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in factor receptor 2–positive and triple-negative primary breast cancers. hepatocellular carcinoma. J Exp Clin Cancer Res 34: 141. J Clin Oncol 33(9): 983–991. Hilmy M, Campbell R, Bartlett JMS, McNicol AM, Underwood MA, Donizy P, Kaczorowski M, Halon A, Leskiewicz M, Kozyra C, Matkowski R McMillan DC (2006) The relationship between the systemic inflammatory (2015) Paucity of tumor-infiltrating lymphocytes is an unfavorable response, tumour proliferative activity, T-lymphocytic infiltration and prognosticator and predicts lymph node metastases in cutaneous COX-2 expression and survival in patients with transitional cell carcinoma melanoma patients. Anticancer Res 35(1): 351–358. of the urinary bladder. Br J Cancer 95(9): 1234–1238. Dushyanthen S, Beavis PA, Savas P, Teo ZL, Zhou C, Mansour M, Darcy PK, Hotta K, Kato Y, Leighl N, Takigawa N, Gaafar RM, Kayatani H, Hirata T, Loi S (2015) Relevance of tumor-infiltrating lymphocytes in breast cancer. Ohashi K, Kubo T, Tabata M, Tanimoto M, Kiura K (2015) Magnitude of BMC Med 13: 202. the benefit of progression-free survival as a potential surrogate marker in Eckl J, Buchner A, Prinz PU, Riesenberg R, Siegert SI, Kammerer R, Nelson PJ, phase 3 trials assessing targeted agents in molecularly selected patients Noessner E (2012) Transcript signature predicts tissue NK cell content with advanced non-small cell lung cancer: systematic review. PLoS One and defines renal cell carcinoma subgroups independent of TNM staging. 10(3): e0121211. J Mol Med 90(1): 55–66. Huang Y, Liao H, Zhang Y, Yuan R, Wang F, Gao Y, Wang P, Du Z (2014) Engels B, Engelhard Victor H, Sidney J, Sette A, Binder David C, Liu Rebecca B, Prognostic value of tumor-infiltrating FoxP3þ T cells in gastrointestinal Kranz David M, Meredith Stephen C, Rowley Donald A, Schreiber H cancers: a meta analysis. PLoS ONE 9(5): e94376. (2013) Relapse or eradication of cancer is predicted by peptide-major Hwang W-T, Adams SF, Tahirovic E, Hagemann IS, Coukos G (2012) histocompatibility complex affinity. Cancer Cell 23(4): 516–526. Prognostic significance of tumor-infiltrating T-cells in ovarian cancer: a Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM, Dengel LT, meta-analysis. Gynecol Oncol 124(2): 192–198. Patterson JW, Slingluff CL (2012) Immunotype and immunohistologic Jochems C, Schlom J (2011) Tumor-infiltrating immune cells and prognosis: characteristics of tumor infiltrating immune cells are associated with the potential link between conventional cancer therapy and immunity. Exp clinical outcome in metastatic melanoma. Cancer Res 72(5): 1070–1080. Biol Med 236(5): 567–579. Eriksson H, Frohm-Nilsson M, Ja¨rås J, Kanter-Lewensohn L, Kjellman P, Kakavand H, Vilain RE, Wilmott JS, Burke H, Yearley JH, Thompson JF, Månsson-Brahme E, Vassilaki I, Hansson J (2015) Prognostic factors in Hersey P, Long GV, Scolyer RA (2015) Tumor PD-L1 expression, immune localized invasive primary cutaneous malignant melanoma: results of a cell correlates and PD-1þ lymphocytes in sentinel lymph node melanoma large population-based study. Br J Dermatol 172(1): 175–186. metastases. Mod Pathol 28(12): 1535–1544. Fortes C, Mastroeni S, Mannooranparampil TJ, Passarelli F, Zappala A, Kang MJ, Kim KM, Bae JS, Park HS, Lee H, Chung MJ, Moon WS, Lee DG, Annessi G, Marino C, Caggiati A, Russo N, Michelozzi P (2015) Tumor- Jang KY (2013) Tumor-infiltrating PD1-positive lymphocytes and infiltrating lymphocytes predict cutaneous melanoma survival. Melanoma FoxP3-positive regulatory T cells predict distant metastatic relapse and Res 25(4): 306–311. survival of clear cell renal cell carcinoma. Transl Oncol 6(3): 282–289. Fraga CA, de Oliveira MV, Domingos PL, Botelho AC, Guimaraes AL, Knief J, Reddemann K, Petrova E, Herhahn T, Wellner U, Thorns C (2016) Teixeira-Carvalho A, Correa-Oliveira R, De Paula AM (2012) Infiltrating High density of tumor-infiltrating B-lymphocytes and plasma cells CD57þ inflammatory cells in head and neck squamous cell carcinoma: signifies prolonged overall survival in adenocarcinoma of the clinicopathological analysis and prognostic significance. Appl esophagogastric junction. Anticancer Res 36(10): 5339–5345. Immunohistochem Mol Morphol 20(3): 285–290. Knol AC, Nguyen JM, Quereux G, Brocard A, Khammari A, Dreno B (2011) ` ` Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G Prognostic value of tumor-infiltrating Foxp3þ T-cell subpopulations in (2011) Prognostic and Predictive Impact of Intra- and Peritumoral metastatic melanoma. Exp Dermatol 20(5): 430–434. Immune Infiltrates. Cancer Res 71(17): 5601–5605. Kogashiwa Y, Yasuda M, Sakurai H, Nakahira M, Sano Y, Gonda K, Ikeda T, Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, Reddy S, Inoue H, Kuba K, Oba S, Ishikawa J, Enoki Y, Matsumura S, Minami K, Kleiner D, Fishbein T, Johnson L, Island E, Satoskar R, Banovac F, Jha R, Ebihara Y, Sugasawa M (2017) PD-L1 expression confers better prognosis Kachhela J, Feng P, Zhang T, Tesfaye A, Prins P, Loffredo C, Marshall J, in locally advanced oral squamous cell carcinoma. Anticancer Res 37(3): Weiner L, Atkins M, He AR (2016) Intratumoral CD3 and CD8 T-cell 1417–1424. densities associated with relapse-free survival in HCC. Cancer Immunol Krpina K, Babarovic E, Jonjic N (2015) Correlation of tumor-infiltrating Res 4(5): 419–430. lymphocytes with bladder cancer recurrence in patients with solitary Gajewski TF, Schreiber H, Fu Y-X (2013) Innate and adaptive immune cells in low-grade urothelial carcinoma. Virchows Archiv 467(4): 443–448. the tumor microenvironment. Nat Immunol 14(10): 1014–1022. Ladanyi A (2015) Prognostic and predictive significance of immune cells Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C (2014) infiltrating cutaneous melanoma. Pigment Cell Melanoma Res 28(5): Towards the introduction of the ‘Immunoscore’ in the classification of 490–500. malignant tumours. J Pathol 232: 199–209. Ladanyi A, Kiss J, Mohos A, Somlai B, Liszkay G, Gilde K, Fejos Z, Gaudi I, Garg K, Maurer M, Griss J, Bruggen MC, Wolf IH, Wagner C, Willi N, Dobos J, Timar J (2011) Prognostic impact of B-cell density in cutaneous Mertz KD, Wagner SN (2016) Tumor-associated B cells in cutaneous melanoma. Cancer Immunol Immunother 60(12): 1729–1738. primary melanoma and improved clinical outcome. Hum Pathol 54: Lee S-J, Lim HJ, Choi YH, Chang YH, Lee WJ, Kim DW, Yoon GS (2013) The 157–164. clinical significance of tumor-infiltrating lymphocytes and microscopic Geissler K, Fornara P, Lautenschlager C, Holzhausen HJ, Seliger B, Riemann satellites in acral melanoma in a Korean population. Ann Dermatol 25(1): D (2015) Immune signature of tumor infiltrating immune cells in renal 61–66. cancer. Oncoimmunology 4(1): e985082. Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, Xu M (2009) The Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, Wu C, Jiang J (2015) Prognostic prognostic value of peritumoral regulatory T cells and its correlation with role of tumor-infiltrating lymphocytes in lung cancer: a meta-analysis. Cell intratumoral cyclooxygenase-2 expression in clear cell renal cell Physiol Biochem 37(4): 1560–1571. carcinoma. BJU Int 103(3): 399–405. Grotz TE, Vaince F, Hieken TJ (2013) Tumor-infiltrating lymphocyte Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, Santarlasci V, response in cutaneous melanoma in the elderly predicts clinical outcomes. Serni S, Cosmi L, Maggi L, Angeli R, Mazzinghi B, Romagnani P, Maggi E, Melanoma Res 23(2): 132–137. Carini M, Romagnani S, Annunziato F (2011) Frequency of regulatory T 458 www.bjcancer.com | DOI:10.1038/bjc.2017.220 Prognostic role of immune cells in cancer BRITISH JOURNAL OF CANCER cells in peripheral blood and in tumour-infiltrating lymphocytes correlates Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, with poor prognosis in renal cell carcinoma. BJU Int 107(9): 1500–1506. Willard-Gallo K, Loi S (2015) The evaluation of tumor-infiltrating Man Y-G, Stojadinovic A, Mason J, Avital I, Bilchik A, Bruecher B, Protic M, lymphocytes (TILs) in breast cancer: recommendations by an Nissan A, Izadjoo M, Zhang X, Jewett A (2013) Tumor-infiltrating International TILs Working Group 2014. Ann Oncol 26(2): 259–271. immune cells promoting tumor invasion and metastasis: existing theories. Santoiemma PP, Powell Jr DJ (2015) Tumor infiltrating lymphocytes in J Cancer 4(1): 84–95. ovarian cancer. Cancer Biol Ther 16(6): 807–820. Mao Y, Qu Q, Chen X, Huang O, Wu J, Shen K (2016) The prognostic value Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating of tumor-infiltrating lymphocytes in breast cancer: a systematic review immunity’s roles in cancer suppression and promotion. Science 331: 1565–1570. and meta-analysis. PLoS ONE 11(4): e0152500. Shankaran V (2001) IFNg and lymphocytes prevent primary tumour Marvel D, Gabrilovich DI (2015) Myeloid-derived suppressor cells in the development and shape tumour immunogenicity. Nature 410: 1107–1111. tumor microenvironment: expect the unexpected. J Clin Invest 125(9): Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, Bajorin DF, 3356–3364. Reuter VE, Herr H, Old LJ, Sato E (2007) CD8 tumor-infiltrating Mei Z, Liu Y, Liu C, Cui A, Liang Z, Wang G, Peng H, Cui L, Li C (2014) lymphocytes are predictive of survival in muscle-invasive urothelial Tumour-infiltrating inflammation and prognosis in colorectal cancer: carcinoma. Proc Natl Acad Sci USA 104(10): 3967–3972. systematic review and meta-analysis. Br J Cancer 110(6): 1595–1605. Sideras K, Biermann K, Verheij J, Takkenberg BR, Mancham S, Hansen BE, Messaoudene M, Perier A, Fregni G, Neves E, Zitvogel L, Cremer I, Chanal J, Schutz HM, de Man RA, Sprengers D, Buschow SI, Verseput MC, Sastre-Garau X, Deschamps L, Marinho E, Larousserie F, Maubec E, Avril Boor PP, Pan Q, van Gulik TM, Terkivatan T, Ijzermans JN, Beuers UH, MF, Caignard A (2015) Characterization of the microenvironment in Sleijfer S, Bruno MJ, Kwekkeboom J (2017) PD-L1, Galectin-9 and CD8þ positive and negative sentinel lymph nodes from melanoma patients. PLoS tumor-infiltrating lymphocytes are associated with survival in One 10(7): e0133363. hepatocellular carcinoma. Oncoimmunology 6(2): e1273309. Mihm Jr. MC, Mule JJ (2015) Reflections on the histopathology of tumor- Sjodahl G, Lovgren K, Lauss M, Chebil G, Patschan O, Gudjonsson S, infiltrating lymphocytes in melanoma and the host immune response. Mansson W, Ferno M, Leandersson K, Lindgren D, Liedberg F, Cancer Immunol Res 3(8): 827–835. Hoglund M (2014) Infiltration of CD3(þ ) and CD68(þ ) cells in bladder Mittal D, Gubin MM, Schreiber RD, Smyth MJ (2014) New insights into cancer is subtype specific and affects the outcome of patients with muscle- cancer immunoediting and its three component phases—elimination, invasive tumors. Urol Oncol 32(6): 791–797. equilibrium and escape. Curr Opin Immunol 27: 16–25. Song H, Wu Y, Ren G, Guo W, Wang L (2015) Prognostic factors of oral Nguyen N, Bellile E, Thomas D, McHugh J, Rozek L, Virani S, Peterson L, mucosal melanoma: histopathological analysis in a retrospective cohort of Carey TE, Walline H, Moyer J, Spector M, Perim D, Prince M, McLean S, 82 cases. Histopathology 67(4): 548–556. Bradford CR, Taylor JM, Wolf GT (2016) Tumor infiltrating lymphocytes Stoll G, Bindea G, Mlecnik B, Galon J, Zitvogel L, Kroemer G (2015) and survival in patients with head and neck squamous cell carcinoma. Meta-analysis of organ-specific differences in the structure of the immune Head Neck 38(7): 1074–1084. infiltrate in major malignancies. Oncotarget 6(14): 11894–11909. Nordfors C, Grun N, Tertipis N, Ahrlund-Richter A, Haeggblom L, Sivars L, Sun DS, Zhao MQ, Xia M, Li L, Jiang YH (2012) The correlation between Du J, Nyberg T, Marklund L, Munck-Wikland E, Nasman A, Ramqvist T, tumor-infiltrating Foxp3þ regulatory T cells and cyclooxygenase-2 Dalianis T (2013) CD8þ and CD4þ tumour infiltrating lymphocytes in expression and their association with recurrence in resected head and neck relation to human papillomavirus status and clinical outcome in tonsillar cancers. Med Oncol 29(2): 707–713. and base of tongue squamous cell carcinoma. Eur J Cancer 49(11): Sun C, Xu J, Song J, Liu C, Wang J, Weng C, Sun H, Wei H, Xiao W, Sun R, 2522–2530. Tian Z (2015) The predictive value of centre tumour CD8(þ ) T cells in Obeid JM, Erdag G, Smolkin ME, Deacon DH, Patterson JW, Chen L, patients with hepatocellular carcinoma: comparison with Immunoscore. Bullock TN, Slingluff CL (2016) PD-L1, PD-L2 and PD-1 expression in Oncotarget 6(34): 35602–35615. metastatic melanoma: correlation with tumor-infiltrating immune cells Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, and clinical outcome. Oncoimmunology 5(11): e1235107. Gruber SB, Gallagher RP, Zanetti R, Rosso S, Dwyer T, Venn A, Ozgur HH, Ercetin AP, Eliyatkin N, Seren A, Kupelioglu A, Ortac R, Kanetsky PA, Groben PA, Hao H, Orlow I, Reiner AS, Luo L, Paine S, Diniz G, Aktas S (2014) Regulatory T cells and their prognostic value in Ollila DW, Wilcox H, Begg CB, Berwick M (2013) Tumor-infiltrating hepatopancreatobiliary tumours. Hepatogastroenterology 61(135): lymphocyte grade in primary melanomas is independently associated with 1847–1851. melanoma-specific survival in the population-based genes, environment Park CK, Kim SK (2017) Clinicopathological significance of intratumoral and and melanoma study. J Clin Oncol 31(33): 4252–4259. peritumoral lymphocytes and lymphocyte score based on the histologic Tu J-F, Ding Y-H, Ying X-H, Wu F-Z, Zhou X-M, Zhang D-K, Zou H, Ji J-S subtypes of cutaneous melanoma. Oncotarget 8(9): 14759–14769. (2016) Regulatory T cells, especially ICOSþ FOXP3þ regulatory T cells, Park JH, Roxburgh CS, McMillan DC (2014) Comment on ‘Tumour- are increased in the hepatocellular carcinoma microenvironment and infiltrating inflammation and prognosis in colorectal cancer: systematic predict reduced survival. Sci Rep 6: 35056. review and meta-analysis’. Br J Cancer 111(12): 2372. Ugel S, De Sanctis F, Mandruzzato S, Bronte V (2015) Tumor-induced Partlova S, Boucek J, Kloudova K, Lukesova E, Zabrodsky M, Grega M, myeloid deviation: when myeloid-derived suppressor cells meet tumor- Fucikova J, Truxova I, Tachezy R, Spisek R, Fialova A (2015) Distinct associated macrophages. J Clin Invest 125(9): 3365–3376. patterns of intratumoral immune cell infiltrates in patients with Wang B, Wu S, Zeng H, Liu Z, Dong W, He W, Chen X, Dong X, Zheng L, HPV-associated compared to non-virally induced head and neck Lin T, Huang J (2015) CD103þ tumor infiltrating lymphocytes predict a squamous cell carcinoma. Oncoimmunology 4(1): e965570. favorable prognosis in urothelial cell carcinoma of the bladder. J Urol Pretscher D, Distel LV, Grabenbauer GG, Wittlinger M, Buettner M, 194(2): 556–562. Niedobitek G (2009) Distribution of immune cells in head and neck Wang Q, Luan W, Warren L, Fiel MI, Blank S, Kadri H, Mandeli J, Hiotis SP cancer: CD8þ T-cells and CD20þ B-cells in metastatic lymph nodes are (2016) Prognostic role of immune cells in hepatitis B-associated associated with favourable outcome in patients with oro- and hepatocellular carcinoma following surgical resection depends on their hypopharyngeal carcinoma. BMC Cancer 9: 292. localization and tumor size. J Immunother 39(1): 36–44. Punt S, Dronkers EA, Welters MJ, Goedemans R, Koljenovic S, Bloemena E, Wansom D, Light E, Thomas D, Worden F, Prince M, Urba S, Chepeha D, Snijders PJ, Gorter A, van der Burg SH, Baatenburg de Jong RJ, Jordanova Kumar B, Cordell K, Eisbruch A, Taylor J, Moyer J, Bradford C, D’Silva N, ES (2016) A beneficial tumor microenvironment in oropharyngeal Carey T, McHugh J, Wolf G (2012) Infiltrating lymphocytes and human squamous cell carcinoma is characterized by a high T cell and low papillomavirus-16—associated oropharyngeal cancer. Laryngoscope IL-17(þ ) cell frequency. Cancer Immunol Immunother 65(4): 393–403. 122(1): 121–127. Saldanha G, Flatman K, Teo KW, Bamford M (2017) A novel numerical Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, Suchak K, scoring system for melanoma tumor-infiltrating lymphocytes has better Webb A, Hampton C, Patel NN, Randall CJ, Cox HJ, Jogai S, Primrose J, prognostic value than standard scoring. Am J Surg Pathol 41(7): 906–914. Piper K, Ottensmeier CH, King EV, Thomas GJ (2014) Tumour- Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, infiltrating lymphocytes predict for outcome in HPV-positive Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, oropharyngeal cancer. Br J Cancer 110(2): 489–500. Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Weiss SA, Han SW, Lui K, Tchack J, Shapiro R, Berman R, Zhong J, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Krogsgaard M, Osman I, Darvishian F (2016) Immunologic heterogeneity www.bjcancer.com | DOI:10.1038/bjc.2017.220 459 BRITISH JOURNAL OF CANCER Prognostic role of immune cells in cancer of tumor-infiltrating lymphocyte composition in primary melanoma. Hum non-muscle-invasive bladder cancer. Int J Clin Exp Pathol 8(9): 11510– Pathol 57: 116–125. 11516. Zhao HQ, Li WM, Lu ZQ, Yao YM (2014) Roles of Tregs in development of Wolf GT, Chepeha DB, Bellile E, Nguyen A, Thomas D, McHugh J (2015) hepatocellular carcinoma: a meta-analysis. World J Gastroenterol 20(24): Tumor infiltrating lymphocytes (TIL) and prognosis in oral cavity 7971–7978. squamous carcinoma: a preliminary study. Oral Oncol 51(1): 90–95. Xu Q, Wang C, Yuan X, Feng Z, Han Z (2017) Prognostic value of tumor- This work is licensed under the Creative Commons infiltrating lymphocytes for patients with head and neck squamous cell carcinoma. Transl Oncol 10(1): 10–16. Attribution-Non-Commercial-Share Alike 4.0 Inter- Zhang L (2003) Intratumoral T cells, recurrence, and survival in epithelial national License. To view a copy of this license, visit http:// ovarian cancer. N Engl J Med 348: 203–213. creativecommons.org/licenses/by-nc-sa/4.0/ Zhang Q, Hao C, Cheng G, Wang L, Wang X, Li C, Qiu J, Ding K (2015) High CD4(þ ) T cell density is associated with poor prognosis in patients with r The Author(s) named above 2017 460 www.bjcancer.com | DOI:10.1038/bjc.2017.220

Journal

British Journal of CancerSpringer Journals

Published: Jul 13, 2017

There are no references for this article.