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Cold Tumors: A Therapeutic Challenge for Immunotherapy

Cold Tumors: A Therapeutic Challenge for Immunotherapy REVIEW published: 08 February 2019 doi: 10.3389/fimmu.2019.00168 Cold Tumors: A Therapeutic Challenge for Immunotherapy 1,2 1,2 1,2 2 Paola Bonaventura , Tala Shekarian , Vincent Alcazer , Jenny Valladeau-Guilemond , 1,2 3 1,2 Sandrine Valsesia-Wittmann , Sebastian Amigorena , Christophe Caux and 1,2,4 Stéphane Depil * 1 2 Centre Léon Bérard, Lyon, France, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France, 3 4 Institut Curie, PSL Research University, INSERM, U932, Paris, France, Université Claude Bernard Lyon 1, Lyon, France Therapeutic monoclonal antibodies targeting immune checkpoints (ICPs) have changed the treatment landscape of many tumors. However, response rate remains relatively low in most cases. A major factor involved in initial resistance to ICP inhibitors is the lack or paucity of tumor T cell infiltration, characterizing the so-called “cold tumors.” In this review, we describe the main mechanisms involved in the absence of T cell infiltration, including lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of homing into the tumor bed. We discuss then the different therapeutic approaches that could turn cold into hot tumors. In this way, specific therapies are proposed according to their mechanism of action. In addition, ‘‘supra-physiological’’ therapies, such as T cell recruiting bispecific antibodies and Edited by: Salem Chouaib, Chimeric Antigen Receptor (CAR) T cells, may be active regardless of the mechanism Institut Gustave Roussy, France involved, especially in MHC class I negative tumors. The determination of the main factors Reviewed by: implicated in the lack of preexisting tumor T cell infiltration is crucial for the development Viktor Umansky, of adapted algorithms of treatments for cold tumors. German Cancer Research Center (DKFZ), Germany Keywords: cold tumors, T cells, tumor antigen, presentation, priming, trafficking, immunotherapy Daniel Olive, Aix Marseille Université, France *Correspondence: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of many tumors, Stéphane Depil inducing durable responses in some cases, Tumor mutational load, CD8 T cell density and stephane.depil@lyon.unicancer.fr Programmed cell Death Ligand−1 (PD-L1) expression have each been proposed as distinct biomarkers of response to PD-1/-L1 antagonists. The lymphocyte infiltration and IFN-γ status Specialty section: may be key factors for effective anti-PD-1/-L1 therapy by defining a “T cell inflamed” phenotype This article was submitted to (“hot tumors”). In contrast, lack of T cells infiltrating the tumor characterizes “non-inflamed” or Cancer Immunity and Immunotherapy, a section of the journal “cold tumors” (in which other immune populations or myeloid cells can however be observed). Frontiers in Immunology Immunological treatment of cold tumors is a great challenge as no adaptive immune response has been set up or maintained. In this review, we discuss the possible issues that the immune system Received: 04 December 2018 Accepted: 21 January 2019 could encounter at different steps of the anti-tumor immune cycle (1), leading to the absence of T Published: 08 February 2019 cell infiltration: lack of tumor antigens, defect in Antigen Presenting Cells (APCs), absence of T cell activation and deficit of homing into the tumor bed (Figure 1). The potential therapeutic strategies Citation: Bonaventura P, Shekarian T, Alcazer V, to overcome these problems will be described in the second part of this review. We will not discuss Valladeau-Guilemond J, here the mechanisms of immune escape developed by inflamed tumors, reviewed elsewhere (2). Valsesia-Wittmann S, Amigorena S, Caux C and Depil S (2019) Cold LACK OF TUMOR ANTIGENS Tumors: A Therapeutic Challenge for Immunotherapy. Tumor antigens can be divided into three main classes: tumor specific antigens (TSA), cancer- Front. Immunol. 10:168. doi: 10.3389/fimmu.2019.00168 germline antigens (CGA), and tumor associated antigens (TAA) (3). TSA are expressed only by Frontiers in Immunology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy cancer cells and not in healthy tissues (4). TSA include mutation- release, associated with different modalities of spontaneous or associated neoantigens (MANA) and viral antigens. MANAs arise induced cancer cell death, may also influence the quality of the from DNA mutation/rearrangement in a gene coding sequence T cell response (13). and play a crucial role in the recognition of tumor cells by CD8 T cells after immune checkpoint treatment (5). Viral antigens ABSENCE OF T CELL may also represent the target for immune recognition of virus- PRIMING/ACTIVATION associated tumors (6). CGA are expressed in tumor cells of different histological origins, but they are silent in normal adult Defective Recruitment of APCs tissues, except in the male germ line and trophoblastic cells The second step of the anti-tumor immune response consists (7). Their expression is associated to the demethylation of their in the presentation of tumor antigens by dendritic cells (DCs), promoter. TAA correspond to antigens with low expression in resulting in the priming and activation of specific effector T normal tissues and overexpressed in tumor cells, like HER2 (8), cells. Several DCs subsets such as classical DCs (type 1 cDC1s or melanocyte differentiation proteins (9). and type 2 cDC2s), Langerhans cells, inflammatory DCs and Tumor mutation burden (TMB) is a quantitative measure plasmacytoid DCs (pDCs) exist and are specialized in different of the total number of mutations per coding area of a tumor functions to shape the immune response and cope with the threat genome that has been shown to predict responses to ICIs in of diversity (14). In particular some evidences exist showing a range of advanced cancers (10). Tumors with a high TMB that a higher ratio of cDC1s over monocytes/macrophages in are believed to express more MANA. Interestingly, a correlation the tumor bed favors protective anti-tumoral adaptive immune between MANA and CGA has been observed (11). However, responses (15). Spranger et al. have also shown in melanoma that even if some tumors are characterized by low expression of both MHC expression and DCs infiltration is associated with T cell MANA and CGA, the quantity of tumor neoantigens does not infiltration (12). seem to be the main limiting factor for the induction of a T cell Among DCs, cDC1s excel at inducing anti-tumoral CD8 T response. A recent study by Spranger et al. analyzed the impact cell responses through cross-presentation of exogenous antigens of the presence of differentiation antigens, CGA and MANA on MHC-I (16–18). A strong correlation between CD8 gene on T cell infiltration in malignant melanoma. They reported transcript and cDC1s markers was observed, suggesting that lack that non-T-cell-inflamed melanomas do not lack antigens for of T cell activation and infiltration in the non-T-cell-inflamed T-cell recognition, arguing for other mechanisms causing the tumor microenvironment is mainly associated with a defective lack of T cell priming and recruitment. Moreover, the number recruitment and activation of cDC1 (19–21). Moreover, recent of neoantigens and the mutational load was still comparable papers published by M. Krummel and C. Reis e Sousa teams between non-T cell-inflamed and T cell-inflamed subtypes in recently demonstrated a critical role of the cross-talk between other solid tumors (12). Finally, the kinetics of tumor antigens cDC1s and NK cells for the CTL infiltration in melanoma FIGURE 1 | Reversing a cold into a hot tumor. Adapted from Chen and Mellman (1). The absence of T cells in the tumor can be due to the lack of tumor antigens, APC deficit, absence of T cell priming/activation and impaired trafficking of T cells to the tumor mass (left panel). Understanding which step of the anti-cancer immune response is not functional in cancers is crucial to adapt therapies to the cancer phenotype. Frontiers in Immunology | www.frontiersin.org 2 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy (22, 23). In mice, several reports have shown that cDC1s are in melanoma. Using a genetically engineered mouse model necessary for the natural rejection of transplanted tumors and for they showed that melanomas arising from mice with active β- the efficiency of anti-tumoral immunotherapies including ICIs or catenin were characterized by an almost complete absence of adoptive transfer of anti-tumoral CD8 T cells (24). both CD8+ T cells and cDC1 subsets (37). A second pathway identified to play a role in T cell exclusion is PI3K pathway activation/PTEN loss. Loss of PTEN in tumor cells in preclinical Lack of T Cell Co-stimulation and models of melanoma was shown to increase the expression of Activation After Antigen Presentation immunosuppressive cytokines, inhibit T cell-mediated tumor The maturation and activation of antigen-presenting DCs is killing and decrease T cell trafficking into tumors. Furthermore, a critical step for activating an efficient T cell-response. In in patients PTEN loss correlated with decreased T cell infiltration this context, the DC activation marker DC-LAMP is a good at tumor sites and inferior outcome after PD-1 inhibitor prognostic marker in solid tumors (25). Naive T cells require therapy (13). PTEN-deficient prostate tumors similarly induce an contact with activated APCs to be primed in an appropriate immunosuppressive tumor microenvironment by upregulating context of “danger signal” (26). APCs expressing Pattern PTPN11/SHP2 and inducing activity of the Jak2-Stat3 pathway Recognition Receptors (PRRs) can be directly activated by (38). Loss of PTEN was recently associated with resistance to Pathogen-Associated Molecular Patterns (PAMPs) or Danger anti-PD1 therapy in metastatic uterine leiomyosarcoma (39) and Associated Molecular Patterns (DAMPs) to become competent to the blockade of this pathway in vivo contributed to an improved prime T cell responses (27). Engagement of PRRs on DCs induces tumor control (13). NF-κB activation, up-regulation of co-stimulatory molecules, Tauriello et al. investigated how genetic alterations and production of cytokines and promotion of cross-priming (28, the tumor microenvironment (TME) interact in a metastatic 29). Various DAMPs are produced by tumor cells undergoing colorectal carcinoma (CRC) model. A Tumor Growth Factor immunological cell death [e.g., calreticulin, HighMobility Group (TGF)-β activity correlating with T cell exclusion and a low Box 1 protein (HMGB1) or Sin3A Associated Protein 130 TMB was described (40). Recently, a study associated a TGF-β (SAP130)] (30). The absence or low production of DAMPs signature of stromal cells with lack of response to anti PD-L1 in could induce a lack of DCs maturation as well as production of the excluded tumor–immune phenotype (41). Blockade of TGF-β immunosuppressive factors such as transforming growth factor in a pancreatic ductal adenocarcinoma model improved the cure beta (TGF-β) leading to the absence of CD4 T cell help (30, 31). rate of mice by decreasing the presence of immune suppressive Recent works demonstrate the importance of the protein Formyl cells in the TME and enhancing CD8+ T cell infiltration within Peptide Receptor 1 (FPR1) expressed by tumoral DCs in the the tumor (42). anthracycline-induced immunogenic cell death. DCs lacking or presenting a variant of FRP1, failed in antigen presentation and activation of T cells, resulting in poor anticancer immune Modified Production of Chemokines and responses and reduced overall survival in breast and colon Cytokines Affecting Cell Trafficking and cancer (32). Activation Stimulation of CD40 on APCs through CD40L expressed on Cytokines and chemokines may influence cell trafficking to the helper CD4+ T cells is another crucial step for the activation of tumor bed. Besides the steady-state influx of immature dendritic APCs to prime CD8 T cells. Moreover, the stimulation of CD40 cells (iDCs) within tissues, chemokines, abundantly secreted on DCs regulates the expression of the co-stimulatory molecules under inflammatory conditions, can provoke influx of iDCs in CD80 and CD86, enhances the production of cytokines (most the tumor bed (43). Lack of those chemokines and the consequent notably IL-12 and IFN-I) and promotes the cross-priming to + reduced influx of iDCs in the tumor bed can be the cause of the exogenous antigens (33). As a consequence, reduced CD8 T cell reduced activation and migration of T cells at the tumor site. responses are largely due to impaired activation of APCs or to the Chemokines acting on iDCs are the Monocyte Chemoattractant absence of co-stimulation. Proteins (CCL2, CCL7, CCL8) as well as CCL3/MIP-1alpha, CCL5/RANTES, and CCL4/MIP-1beta (44). Cytokines are also DEFICIT OF HOMING TO THE TUMOR BED necessary to generate active DCs: as an example type I interferon (IFN-I) produced by DCs can act in an autocrine manner to CD8 T Cell Exclusion by the generate fully active DC1s (45). Moreover, DC1s are a source of Immunosuppressive Peritumoral Stroma CXCL-9/10 and their absence lead to a reduced production of and Tumor Cell Alterations these chemokines (20). The chemokine CXCL16, produced by When DCs are mature and T-cells correctly primed and activated, DCs, and its receptor CXCR6 for example have been associated + + the access of T cell to the tumor bed could be compromised by the with an increased CD4 and CD8 T cell recruitment and a good stromal compartment (34). The exclusion of CD8 T cells from prognosis in CRC (46). The disruption of the CXCL16/CXCR6 the vicinity of cancer cells was shown to correlate with a poor pathway could lead to a reduced tumor T cell infiltration. long-term clinical outcome in colorectal cancer, ovarian cancer The deregulation of trafficking can directly involve T cells: and pancreatic ductal adenocarcinoma (35, 36). Interestingly, DCs-activated T cells against tumor antigens have to reach Spranger et al. reported an inverse relationship between intrinsic the tumor bed to perform their anti-cancer activity. Tumors β-catenin signaling of tumor cells and intra-tumoral T cells can disrupt chemokine expression to deregulate the immune Frontiers in Immunology | www.frontiersin.org 3 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy response and chemokines involved in effector T-cell recruitment of Th1-type chemokines in tumor cells, which is negatively + + is significantly reduced in tumors lacking a CD8 T-cell infiltrate. associated with CD8 T cells in tumors and patient outcome (48). CXCL9 and CXCL10 (CXCL11 in humans) are key chemokines There is thus a strong rationale to combine epigenetic therapy in the recruitment of CD8+ T cells engaging the CXCR3 on and immunotherapy and many clinical trials are currently their surface and their production is generally deregulated in ongoing (55). “non-inflamed” tumors (47). CXCL9/10 can be produced by the tumor cell itself where a methylation of chemokine genetic NK Cell-Based Approaches loci results in a reduced CD8 T cell infiltration. The use Natural killer (NK) cells are lymphocytes of the innate immune of demethylating agents restores chemokine production and system able to recognize and kill tumors lacking self-MHC T-cell recruitment, showing that epigenetic modification is a class I molecules, by recognizing stressed cells. For this reason mechanism of tumor escape which could lead to the lack NK approaches could be suitable in the absence of tumor of immune cells infiltration (48). Tumors can also alter the antigens or in case of deficient antigen presentation machinery chemistry of certain chemokines to preferentially recruit myeloid (e.g., lack of MHC class I). While a large portion of cancer cells: as an example the nitrosylated CCL2 eliminates the ability immunotherapies focus on targeting T cells, NK cell system to recruit CTLs and Th1 effector cells (49), while selectively for therapeutic intervention stays relatively underexplored. Nevertheless, different NK cell-based approaches have been recruiting myeloid dendritic stem cells (MDSCs) to tumor sites. described, such as ex vivo activated NK cells or NK cells transduced with a chimeric antigen receptor (CAR) to target THERAPEUTIC APPROACHES specific cancer cell surface antigen (56, 57). Antibodies-mediated targeting of NK activating receptors such as NKG2D and NKP46, Different therapeutic approaches can theoretically be used to or inhibitory receptors such as KIR and NKG2a, is under overcome the absence of T cell infiltration in tumors. These deep investigation (58). Lirilumab is a fully human antibody strategies are summarized in Figure 2. The demonstration that directed against KIR2DL-1,-2,-3 inhibitory receptors expressed these therapies can effectively transform a cold into hot tumor predominantly on NK cells and is being tested in combination remains to be done in the clinic in most instances. with ipilimumab or nivolumab for the treatment of patients bearing advanced solid malignancies (59). Specific Therapies for Tumors Expressing Few Antigens Specific Therapies for Tumors With Demethylating Agents Defective Priming or T Cell Activation It has been shown that DNA methyltransferase inhibitors Chemo/Radiotherapy Inducing Immunogenic Cell (DNMTi) and histone deacetylase inhibitors can enhance the expression of tumor antigens and components of antigen Death (ICD) processing and presenting machinery pathways, as well as other Several chemotherapies were found to work mainly in immune related genes (50, 51). These agents can also induce immunocompetent subjects, accumulating evidences that tumor the expression of retroelements such as endogenous retroviruses inhibition partially relies on the immune system competence (ERVs), usually silent and able to induce a type I IFN response and not only on the direct anti-tumor toxicity of chemotherapy (52). Epigenetic drugs have been reported to induce transcription (60). In this regard ICD inducing chemotherapeutic agents from normally repressed ERV LTR, that may cause ectopic can be classified within cancer immunotherapy strategies. expression of transcripts with canonical or novel open reading Radiotherapy was initially designed to selectively kill tumor frames, leading to the production of immunogenic peptides cells within the irradiated field. However, emerging evidence (53, 54). DNMTi and Histone-lysine N-methyltransferase EZH2 indicates that radiotherapy, by inducing ICD, harnesses the inhibitors have also been shown to reverse epigenetic silencing host’s immune system to attack the tumor cells outside the FIGURE 2 | Specific and common approaches to overcome the absence of T cells in tumors. According to the mechanism involved in the lack of T cell infiltration in tumors, specific therapies can be selected. In the case of MHC-I negative tumors or if specific therapies are not sufficient, “supra-physiological therapies” can be used. Frontiers in Immunology | www.frontiersin.org 4 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy irradiation field, explaining the “abscopal” effect (regression of to activate and “license” DCs to prime effective cytotoxic CD8 tumor lesions outside the irradiation field) (61). Based on this T cell responses. CD40 signaling can also be effectively triggered rationale, many trials are ongoing to combine chemotherapy using agonistic antibodies or CD40L, thus bypassing the need and radiotherapy with PD-1/PD-L1 antibodies. Of note, for CD4 helper T cells (73). In preclinical studies, agonistic the same rationale also applies to antibody-drug conjugates CD40 antibodies have demonstrated T cell-dependent anti- (ADCs) with cytotoxic payloads capable of inducing ICD, tumor activity, in particular in combination with conventional justifying the initiation of clinical trials combining ADCs and chemotherapy and immune checkpoint inhibitors (ICIs). Many immunotherapy (62). CD40 antibodies are under clinical development (74). Toxicity profile is acceptable in monotherapy and combination trials are Oncolytic Viruses ongoing (75). Oncolytic viruses are common viruses that can selectively target, Tumor Vaccines replicate in and destroy cancer cells (63). Most oncolytic viruses The therapeutic breakthrough provided by ICIs and the can induce cancer cell death and directly eliminate tumor demonstration of the role of MANA in T-cell mediated cells, but they also initiate systemic immune responses through antitumor response have paved the way for a next generation different mechanisms such as induction of ICD and release of personalized cancer vaccines based on the use of MANA of danger signals (DAMPs) and tumor antigens from virus- specific of the tumor. Preclinical results showed induction of infected cells. They also release viral PAMPs contributing to efficient antitumor response and clinical trials providing a clinical APCs maturation that conduct to activation of antigen-specific + + proof of concept in melanoma have been published (76–78). A CD4 and CD8 T cell responses (64). Moreover, the infected + + specific CD8 and CD4 T cell immune response characterized cells are directly recognized by the innate immune system by the induction or the amplification of a preexisting response such as NK cells or macrophages (65). It has been recently against MANA has been shown. Encouraging clinical activity shown in a melanoma phase I trial that use of oncolytic seems to be associated but larger trials are awaited to firmly viro-therapy was able to convert a cold into hot tumor, as demonstrate the clinical activity of this therapeutic approach. patients with a low level of immune cell infiltrate and a Theoretically, cancer vaccines may either reinforce the activity negative IFNγ signature before treatment responded well to and therapeutic margin of ICIs by increasing the number of the combination of talimogene laherparepvec with the PD-1 specific effector T cells, or convert cold into inflamed tumors. antagonist pembrolizumab (66). The potential limitations are the availability of T cell repertoire in cancer patients and the risk of specific loss of heterozygosity PRR Agonists (LOH) of the HLA presenting MANA in advanced metastatic PRRs consist of five families including Toll-like receptors (TLRs), tumors (79). RIG-I-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors Specific Therapies for Tumors With (CLRs), and cytoplasmic DNA sensors. PRRs agonists have notably the ability to activate PRR pathways inducing antigen Impaired T Cell Trafficking to the Tumor presentation by myeloid cells residing in the tumor micro- TGF-β Blocking Antibodies and TGF-β-Receptor environment (67–69). Antagonists TLR agonists showed controversial results in pre-clinical TGF-β has been involved in cell proliferation, angiogenesis, studies by either promoting or inhibiting tumor progression epithelial-to-mesenchymal transition, immune infiltration, depending on the TLR and the tumor type (70). Multiple TLR metastases dissemination, and drug resistance (80). Of note agonists are currently in clinical development. As an example, TGF-β produced by the tumor cells mediates alterations in the intra-tumoral injections of a TLR-9 agonist, the CpG-rich tumor-associated pDCs functions, e.g., impaired capacity to oligonucleotide PF-3512676, showed significant activity in both produce IFN type I, leading to a lacking/unbalanced T cell injected and non-injected lesions of B- and T-cell lymphomas recruitment (81, 82). Recent reports have shown that TGF- when used concomitantly with low-dose (2 × 2 Gy) local β in the peritumoral area was a major factor involved in irradiation (71). T cell exclusion from the tumor. Mariathasan et al. used a STING has been shown to play an important role in the innate preclinical model recapitulating T cell exclusion and showed immune response against cancer. In the TME, tumor cell DNA that combination of a TGFβ blocking antibody with a PD-L1 detected by APCs is correlated with activation of STING pathway antibody induced T cell penetration into the center of tumors, that leads to IFN-β production (25), enhancing CD8 T cell allowing anti-tumor immunity and tumor regression (41). priming and trafficking of effector T cells. One STING agonist, Several TGF-β antibodies or small molecules TGF-β-receptor ADU-S100 (Aduro Biotech/Novartis), is currently evaluated antagonists are in clinical development and could be tested in in phase I clinical trial by intra-tumoral administration in this setting. cutaneously accessible tumors (72). Anti-angiogenic Therapies CD 40 Agonistic Antibodies The clinical activity of anti-angiogenic drugs is modest when CD40 is broadly expressed on immune cells, predominantly on used as single agent. However, it has been shown that DCs, B cells and macrophages. A major role of CD40 signaling is anti-angiogenic drugs normalize the tumor vasculature and Frontiers in Immunology | www.frontiersin.org 5 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy induce the upregulation of the leukocyte adhesion molecules demonstrate and will probably require optimization of CAR ICAM-1 and VCAM-1 on tumor endothelial cells (83), leading functions [for review see (93)]. to increased T cell infiltration (84). These therapies may thus T-Cell Recruiting Bi-specific Antibodies represent a treatment of choice for tumors characterized by T Bi-specific antibodies (bsAbs) are engineered antibodies that cells blocked in the periphery of the tumor in order to enhance can bind two different antigens. One of the main strategies in intratumoral penetration of T cells. It has been shown in the the development of bsAbs is the recruitment and activation of clinic that anti-angiogenic therapies could synergize with ICIs in immune effector T cells by targeting CD3 domain of the TCR metastatic melanoma (85). complex (T-cell recruiting bsAbs) together with another antigen abnormally expressed on the tumor cell surface. The approval of Immunocytokines catumaxomab (anti-epitelial cell adhesion molecule EpCAM and Cytokines such as IL-2, TNF, IL-12 mediate the influx and anti-CD3) and blinatumomab (anti-CD19 and anti-CD3) has expansion of leukocytes at the tumor site. However, these become a major milestone in the development of bsAbs. BsAbs cytokines, and especially IL-12, induce significant toxicity when can be divided into two categories: immunoglobulin G (IgG)- administrated systemically in clinical trials (86). Next generation like molecules and non-IgG-like molecules. Non-IgG-like bsAbs immunocytokines combining a fragment from a specific tumor are smaller in size, leading to enhanced tissue penetration, but antigen antibody with a modified cytokine are being developed shorter half-life (94). Currently, more than 60 different bsAbs with the aim of activating specifically the immune system formats exist, some of them making their way into clinical inside the tumor to reduce systemic side effects. For example, trials. As for CAR T-cells, activity of T cell-recruiting bsAbs is cergutuzumab amunaleukin (CEA-IL2v), is a novel monomeric not dependent on MHC class I expression on tumor cells and CEA-targeted immunocytokine that comprises a single IL- both approaches represent thus very promising treatments for 2 variant (IL2v) moiety with abolished CD25 binding (to MHC I-negative cold tumors. It is however not know whether avoid activation of regulatory T cells) fused to the C-terminus a minimum threshold of T cells inside the tumor is required for of a high affinity bivalent carcinoembryonic antigen (CEA)- the activity of bsAb, alone or in combination with other therapies. specific antibody devoid of Fc-mediated effector functions. A comparison between CAR T cells and T-cell recruiting bsAbs A superior efficacy over the respecting monotherapies was is proposed in Table 1. observed with CEA-IL-2v in combination with PD-L1 antibody and ADCC competent antibodies in CEA-positive solid tumor models (87). PERSPECTIVES Changing the natural history of a tumor characterized by Therapeutic Approaches Active in Different the absence of T cells remains a great therapeutic challenge. Immune Contexts However, as discussed above, many therapeutic approaches can Adoptive T Cell Therapy and Chimeric Antigen be evaluated in this context. A major issue will be to determine Receptor (CAR) T Cells the origin of this lack of T cell response to adapt the therapy to the Historically, cell-based therapies have focused on cytotoxic T physiology of the tumor. Figure 2 summarizes the possibilities of cells targeting MHC-restricted antigens. This approach remains treatment according to this tumor context. promising, in particular with the development of T cell Conventional anticancer approaches like chemotherapy receptor (TCR)-engineered T cells (88) and improvement of and radiotherapy have still a room in the therapeutic tumor infiltrating lymphocytes (TILs) infusion (89). However, armamentarium, not only to potentially induce ICD but their efficacy may be limited by the tendency of tumors to also to reduce the tumor burden and thus potentially decrease downregulate MHC molecules. CARs are engineered receptors the selection of immune-resistant clones. In other cases, “in made of the combination of an antigen binding domain of a situ” vaccination using PRR or CD40 agonists may be used to monoclonal antibody specific for a cancer antigen (not MHC induce a specific immune antitumor response against naturally restricted) together with an intracellular domain of the CD3-zeta presented tumor antigens. Personalized cancer vaccines also chain (90). CAR T cells responses can be further enhanced by represent a very promising strategy especially in highly mutated addition of costimulatory domains, such as CD28 and CD137 tumors. Finally, “supra-physiological” approaches like CAR (4-IBB) to support the expansion and persistence of genetically T cells or T-cell recruiting bsAbs could be efficient in tumors engineered cells in vivo (91). The reinfusion of CAR T-cells is characterized by the absence of MHC expression or even LOH preceded by a “lymphodepleting” chemotherapy regimen used to of the HLA alleles presenting tumor antigens. It is likely that physically create enough space for the expansion and persistence in the near future, algorithms of treatment will be developed of CAR T cell clones. Over the past decade multiple tumor to adapt the therapeutic strategy to the immune context of antigens have been targeted by CARs. Outstanding activity of the tumor, considering also space and time evolution for CAR T cells targeting CD19 has been observed in hematological adequate sequential strategies. At the end, while the efficacy malignancies, in particular in acute lymphoblastic leukemia and of the therapy in inflamed tumors depends principally in the Diffuse Large B cell lymphoma with two CAR T-cell therapies remove of the breaks induced by the immune activation itself, approved by the Food and Drug Administration (FDA) in 2017 the conversion of a cold into an inflamed tumor will require a (92). The clinical activity of CAR in solid tumors is still to prior combination of therapies to induce immune infiltration Frontiers in Immunology | www.frontiersin.org 6 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy TABLE 1 | Comparison between CAR T-cells and T-cell recruiting bi-specific antibodies. CAR T-Cells Bi-specific antibodies Mechanism of - Direct cancer antigen recognition - Recruitment of immune effector T cells by their CD3 with another action - Non MHC-restricted antigen expressed on the tumor cell - Does not require pre-existing T cell infiltration, independent of - Non MHC-restricted receiver T cell characteristics - May be more dependent on quantity/quality of patients’ T cells Administration - Single administration - Repeated administration (continuous infusion for non-IgG-like) - Long half-life (months/years) - Short/intermediate half-life (hours/days) Tissue - Homing of the T cells for blood, lymph nodes, and bone marrow - Non IgG like: enhanced tissue penetration penetration Toxicity - Acute reversible neurotoxicity (CD19) - Lower toxicity expected - Cytokine release syndrome (CRS) - Acute reversible neurotoxicity (CD19) - Cytokine release syndrome (CRS) Main diseases - Outstanding activity in some hematological malignancies: B cell - B cell acute lymphoblastic leukemia (CD19) acute lymphoblastic leukemia, Diffuse Large B cell lymphoma - Clinical trials for many solid tumors including colorectal, ovarian, (CD19) breast and prostate cancer - Clinical trials in solid tumors Other - Clinical activity in solid tumors is still to demonstrate - Clinical activity in solid tumors is still to demonstrate limitations - Immunosuppressive microenvironment (rationale for - Immunosuppressive microenvironment (rationale for combination combination with ICIs or use of optimized CAR T-cells) with ICIs) - Target specificity: risk of escape by loss of the target - Target specificity: risk of escape by loss of the target Cost and - Long process, manufacturing issues - Immediate availability, less manufacturing and regulatory issues +++ + availability - Cost - Cost and then different immune checkpoint modulators to remove FUNDING the breaks. This work was supported by grants from Programme de Recherche Translationnelle en Cancérologie INCa-DGOS (INCa PRT-K2017-072), the Rhône comity of the Ligue AUTHOR CONTRIBUTIONS Contre le Cancer, the SIRC project (LYRICAN, INCa- PB, TS, VA, JV-G, and SD contributed to the DGOS-Inserm_12563), and the LABEX DEVweCAN writing. SD and CC contributed to the conception. (ANR-10-LABX-0061) of the University of Lyon, within SV-W, SA, CC, and SD participated in the lecture the program Investissements d’Avenir organized by the French and corrections. National Agency (ANR). REFERENCES ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med. (1995) 181: 2109–17. 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity 9. Coulie PG, Brichard V, Van Pel A, Wölfel T, Schneider J, Traversari C, et al. cycle. Immunity (2013) 39:1–10. doi: 10.1016/j.immuni.2013.07.012 A new gene coding for a differentiation antigen recognized by autologous 2. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. (1994) 180:35– in the tumor microenvironment. Nat Immunol. (2013) 14:1014–22. 42. doi: 10.1038/ni.2703 10. Yarchoan M, Johnson BA, Lutz ER, Laheru DA, Jaffee EM. Targeting 3. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and neoantigens to augment antitumour immunity. Nat Rev Cancer (2017) response rate to PD-1 Inhibition. N Engl J Med. (2017) 377:2500–1. 17:209–222. doi: 10.1038/nrc.2016.154 doi: 10.1056/NEJMc1713444 11. Ilyas S, Yang JC. Landscape of tumor antigens in T-cell immunotherapy. J 4. Kelderman S, Kvistborg P. Tumor antigens in human cancer Immunol. (2015) 195:5117–22. doi: 10.4049/jimmunol.1501657 control. Biochim Biophys Acta BBA Rev Cancer (2016) 1865:83–9. 12. Spranger S, Luke JJ, Bao R, Zha Y, Hernandez KM, Li Y, et al. Density of doi: 10.1016/j.bbcan.2015.10.004 immunogenic antigens does not explain the presence or absence of the T-cell– 5. Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour inflamed tumor microenvironment in melanoma. Proc Natl Acad Sci USA. antigens recognized by T lymphocytes: at the core of cancer (2016) 113:E7759–68. doi: 10.1073/pnas.1609376113 immunotherapy. Nat Rev Cancer (2014) 14:135–46. doi: 10.1038/nrc 13. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of 3670 PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6. Mitch L. Mutation Burden Predicts Anti-PD-1 Response. Cancer Discov. (2016) 6:202–216. doi: 10.1158/2159-8290.CD-15-0283 (2018) 8:258. doi: 10.1158/2159-8290.CD-NB2018-005 14. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: 7. Chomez P, De Backer O, Bertrand M, De Plaen E, Boon T, Lucas S. An ontogeny and function of dendritic cells and their subsets in the steady overview of the MAGE gene family with the identification of all human state and the inflamed setting. Annu Rev Immunol. (2013) 31:563–604. members of the family. Cancer Res. (2001) 61:5544–51. doi: 10.1146/annurev-immunol-020711-074950 8. Fisk B, Blevins TL, Wharton JT, Ioannides CG. Identification of an 15. Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, immunodominant peptide of HER-2/neu protooncogene recognized by et al. Dendritic cells, monocytes and macrophages: a unified nomenclature Frontiers in Immunology | www.frontiersin.org 7 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy based on ontogeny. Nat Rev Immunol. (2014) 14:571–8. doi: 10.1038/ high levels of self/tumor antigen-specific CD8+ T cells in patients with nri3712 melanoma. J Immunol. (2005) 175:6169–76. doi: 10.4049/jimmunol.175.9. 16. Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, 6169 et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique 35. Lohneis P, Sinn M, Bischoff S, Jühling A, Pelzer U, Wislocka L, et al. myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. Cytotoxic tumour-infiltrating T lymphocytes influence outcome in resected (2010) 207:1247–60. doi: 10.1084/jem.20092140 pancreatic ductal adenocarcinoma. Eur J Cancer (2017) 83:290–301. 17. Bachem A, Güttler S, Hartung E, Ebstein F, Schaefer M, Tannert A, et al. doi: 10.1016/j.ejca.2017.06.016 Superior antigen cross-presentation and XCR1 expression define human 36. Peranzoni E, Lemoine J, Vimeux L, Feuillet V, Barrin S, Kantari-Mimoun CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J Exp C, et al. Macrophages impede CD8 T cells from reaching tumor cells and Med. (2010) 207:1273–81. doi: 10.1084/jem.20100348 limit the efficacy of anti–PD-1 treatment. Proc Natl Acad Sci USA. (2018) 18. Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, 115:E4041–50. doi: 10.1073/pnas.1720948115 et al. Host type I IFN signals are required for antitumor CD8+ T cell 37. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin responses through CD8α+ dendritic cells. J Exp Med. (2011) 208:2005–16. signalling prevents anti-tumour immunity. Nature (2015) 523:231–5. doi: 10.1084/jem.20101159 doi: 10.1038/nature14404 19. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, 38. Toso A, Revandkar A, Di Mitri D, Guccini I, Proietti M, Sarti M, et al. et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by cytotoxic T cell immunity. Science (2008) 322:1097–100. doi: 10.1126/science. activating the senescence-associated antitumor immunity. Cell Rep. (2014) 1164206 9:75–89. doi: 10.1016/j.celrep.2014.08.044 20. Spranger S, Dai D, Horton B, Gajewski TF. Tumor-residing Batf3 39. George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, Shukla S, dendritic cells are required for effector t cell trafficking and adoptive et al. Loss of PTEN Is Associated with resistance to Anti-PD-1 t cell therapy. Cancer Cell (2017) 31:711–23.e4. doi: 10.1016/j.ccell.2017. checkpoint blockade therapy in metastatic uterine leiomyosarcoma. 04.003 Immunity (2017) 46:197–204. doi: 10.1016/j.immuni.2017. 21. Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack 02.001 JL, Erle DJ, et al. Dissecting the tumor myeloid compartment 40. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia- reveals rare activating antigen-presenting cells critical for T cell Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically immunity. Cancer Cell (2014) 26:638–52. doi: 10.1016/j.ccell.2014. reconstituted colon cancer metastasis. Nature (2018) 554:538–43. 09.007 doi: 10.1038/nature25492 22. Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, 41. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. Sammicheli S, et al. NK cells stimulate recruitment of cDC1 into the tumor TGFβ attenuates tumour response to PD-L1 blockade by contributing to microenvironment promoting cancer immune control. Cell (2018) 172:1022– exclusion of T cells. Nature (2018) 554:544–8. doi: 10.1038/nature25501 37.e14. doi: 10.1016/j.cell.2018.01.004 42. Soares KC, Rucki AA, Kim V, Foley K, Solt S, Wolfgang CL, et al. 23. Barry KC, Hsu J, Broz ML, Cueto FJ, Binnewies M, Combes AJ, et al. A TGF-β blockade depletes T regulatory cells from metastatic pancreatic natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor tumors in a vaccine dependent manner. Oncotarget (2015) 6:43005–15. microenvironments. Nat Med. (2018) 24:1178–91. doi: 10.1038/s41591-018- doi: 10.18632/oncotarget.5656 0085-8 43. Randolph GJ, Ochando J, Partida-Sánchez S. Migration of dendritic cell 24. Sánchez-Paulete AR, Cueto FJ, Martínez-López M, Labiano S, Morales- subsets and their precursors. Annu Rev Immunol. (2008) 26:293–316. Kastresana A, Rodríguez-Ruiz ME, et al. Cancer immunotherapy with doi: 10.1146/annurev.immunol.26.021607.090254 immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies 44. Luther SA, Cyster JG. Chemokines as regulators of T cell differentiation. Nat requires BATF3-dependent dendritic cells. Cancer Discov. (2016) 6:71–9. Immunol. (2001) 2:102–7. doi: 10.1038/84205 doi: 10.1158/2159-8290.CD-15-0510 45. Montoya M, Schiavoni G, Mattei F, Gresser I, Belardelli F, Borrow P, 25. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung et al. Type I interferons produced by dendritic cells promote their MYK, et al. STING-dependent cytosolic DNA sensing mediates innate phenotypic and functional activation. Blood (2002) 99:3263–3271. immune recognition of immunogenic tumors. Immunity (2014) 41:830–42. doi: 10.1182/blood.V99.9.3263 doi: 10.1016/j.immuni.2014.10.017 46. Hojo S, Koizumi K, Tsuneyama K, Arita Y, Cui Z, Shinohara K, et al. High- 26. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez level expression of chemokine CXCL16 by tumor cells correlates with a good M, Poulot V, et al. Long-term survival for patients with non- prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. small-cell lung cancer with intratumoral lymphoid structures. Cancer Res. (2007) 67:4725–31. doi: 10.1158/0008-5472.CAN-06-3424 J Clin Oncol. (2008) 26:4410–7. doi: 10.1200/JCO.2007. 47. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff 15.0284 C, et al. Chemokine expression in melanoma metastases associated 27. Akira S, Uematsu STO. Pathogen recognition and innate immunity. Cell with CD8+ T-cell recruitment. Cancer Res. (2009) 69:3077–85. (2006) 124:783–801. doi: 10.1016/j.cell.2006.02.015 doi: 10.1158/0008-5472.CAN-08-2281 28. Janeway CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 48. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. (2002) 20:197–216. doi: 10.1146/annurev.immunol.20.083001.084359 Epigenetic silencing of TH1-type chemokines shapes tumour immunity and 29. Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol. (2006) immunotherapy. Nature (2015) 527:249–53. doi: 10.1038/nature15520 6:476–83. doi: 10.1038/nri1845 49. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, et al. Chemokine 30. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp death in cancer therapy. Annu Rev Immunol. (2013) 31:51–72. Med. (2011) 208:1949–62. doi: 10.1084/jem.20101956 doi: 10.1146/annurev-immunol-032712-100008 50. Srivastava P, Paluch BE, Matsuzaki J, James SR, Collamat-Lai G, Karbach 31. Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic J, et al. Immunomodulatory action of SGI-110, a hypomethylating cell death. Nat Rev Immunol. (2009) 9:353–63. doi: 10.1038/nri2545 agent, in acute myeloid leukemia cells. Leuk Res. (2014) 38:1332. 32. Vacchelli E, Ma Y, Baracco EE, Sistigu A, Enot DP, Pietrocola F, doi: 10.1016/j.leukres.2014.09.001 et al. Chemotherapy-induced antitumor immunity requires formyl peptide 51. Dunn J, Rao S. Epigenetics and immunotherapy: the current state receptor 1. Science (2015) 350:972–8. doi: 10.1126/science.aad0779 of play. Mol Immunol. (2017) 87:227–39. doi: 10.1016/j.molimm.2017. 33. Ridge JP, Di Rosa FMP. A conditioned dendritic cell can be a temporal 04.012 bridge between a CD4+ T-helper and a T-killer cell. Nature (1998) 393:474–8. 52. Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, doi: 10.1038/30989 et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer 34. Rosenberg SA, Sherry RM, Morton KE, Scharfman WJ, Yang JC, Topalian via dsRNA including endogenous retroviruses. Cell (2015) 162:974–86. SL, et al. Tumor progression can occur despite the induction of very doi: 10.1016/j.cell.2015.07.011 Frontiers in Immunology | www.frontiersin.org 8 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy 53. Brocks D, Schmidt CR, Daskalakis M, Jang HS, Shah NM, Li D, et al. DNMT 74. Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, et al. Phase I and HDAC inhibitors induce cryptic transcription start sites encoded in long study of the CD40 agonist antibody CP-870,893 combined with carboplatin terminal repeats. Nat Genet. (2017) 49:1052–60. doi: 10.1038/ng.3889 and paclitaxel in patients with advanced solid tumors. Oncoimmunology 54. Licht JD. DNA Methylation inhibitors in cancer therapy: the immunity (2013) 2:e23033. doi: 10.4161/onci.23033 dimension. Cell (2015) 162:938–9. doi: 10.1016/j.cell.2015.08.005 75. Vonderheide RH. The immune revolution: a case for priming, not 55. Chiappinelli KB, Zahnow CA, Ahuja N, Baylin SB. Combining epigenetic checkpoint. Cancer Cell (2018) 33:563–9. doi: 10.1016/j.ccell.2018. and immune therapy to combat cancer. Cancer Res. (2016) 76:1683. 03.008 doi: 10.1158/0008-5472.CAN-15-2125 76. Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, et al. An immunogenic 56. Zhang C, Oberoi P, Oelsner S, Waldmann A, Lindner A, Tonn T, personal neoantigen vaccine for patients with melanoma. Nature (2017) et al. Chimeric antigen receptor-engineered NK-92 cells: an off-the- 547:217–221. doi: 10.1038/nature22991 shelf cellular therapeutic for targeted elimination of cancer cells and 77. Sahin U, Derhovanessian E, Miller M, Kloke B-P, Simon P, Löwer M, et al. induction of protective antitumor immunity. Front Immunol. (2017) 8:533. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic doi: 10.3389/fimmu.2017.00533 immunity against cancer. Nature (2017) 547:222–6. doi: 10.1038/nature 57. Chu J, Deng Y, Benson DM, He S, Hughes T, Zhang J, et al. CS1-specific 23003 chimeric antigen receptor (CAR)-engineered natural killer cells enhance 78. Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal in vitro and in vivo anti-tumor activity against human multiple myeloma. J, Petti AA, et al. Cancer immunotherapy. A dendritic cell vaccine Leukemia (2014) 28:917–27. doi: 10.1038/leu.2013.279 increases the breadth and diversity of melanoma neoantigen- 58. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer specific T cells. Science (2015) 348:803–8. doi: 10.1126/science. immunotherapy and new immunomodulatory targets. Nat Rev Drug aaa3828 Discov. (2015) 14:561–84. doi: 10.1038/nrd4591 79. McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK, Wilson GA, 59. Aranda F, Vacchelli E, Eggermont A, Galon J, Fridman WH, Zitvogel L, et al. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Trial watch: immunostimulatory monoclonal antibodies in cancer therapy. Cell (2017) 171:1259–71.e11. doi: 10.1016/j.cell.2017.10.001 Oncoimmunology (2014) 3:e27297. doi: 10.4161/onci.27297 80. Gramont A de, Faivre S, Raymond E. Novel TGF-β inhibitors ready 60. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden for prime time in onco-immunology. Oncoimmunology (2017) 6:e1257453. SF, et al. Leukocyte complexity predicts breast cancer survival and doi: 10.1080/2162402X.2016.1257453 functionally regulates response to chemotherapy. Cancer Discov. (2011) 81. Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A, doi: 10.1158/2159-8274.CD-10-0028 et al. Quantitative and functional alterations of plasmacytoid dendritic cells 61. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin contribute to immune tolerance in ovarian cancer. Cancer Res. (2011) Radiat Oncol. (2015) 25:11–7. doi: 10.1016/j.semradonc.2014.07.005 71:5423–34. doi: 10.1158/0008-5472.CAN-11-0367 62. Parslow AC, Parakh S, Lee FT, Gan HK, Scott AM. Antibody- 82. Sisirak V, Faget J, Vey N, Blay JY, Ménétrier-Caux C, Caux C, drug conjugates for cancer therapy. Biomedicines (2016) 4:14 et al. Plasmacytoid dendritic cells deficient in IFNα production doi: 10.3390/biomedicines4030014 promote the amplification of FOXP3+ regulatory T cells 63. Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol. (2012) and are associated with poor prognosis in breast cancer 30:658–70. doi: 10.1038/nbt.2287 patients. Oncoimmunology (2013) 2:e22338: doi: 10.4161/onci. 64. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class 22338 of immunotherapy drugs. Nat Rev Drug Discov. (2015) 14:642–62. 83. Kandalaft LE, Motz GT, Busch J, Coukos G. Angiogenesis and the tumor doi: 10.1038/nrd4663 vasculature as antitumor immune modulators: the role of vascular endothelial 65. Seth RB, Sun L, Chen ZJ. Antiviral innate immunity pathways. Cell Res. (2006) growth factor and endothelin. Curr Top Microbiol Immunol. (2011) 344:129– 16:141–7. doi: 10.1038/sj.cr.7310019 48. doi: 10.1007/82_2010_95 66. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin 84. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg O, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration SA. Antiangiogenic agents can increase lymphocyte infiltration into and improves anti-PD-1 immunotherapy. Cell (2017) 170:1109–19.e10. tumor and enhance the effectiveness of adoptive immunotherapy of doi: 10.1016/j.cell.2017.08.027 cancer. Cancer Res. (2010) 70:6171–80. doi: 10.1158/0008-5472.CAN- 67. Bevers RFM, Kurth K-H, Schamhart DHJ. Role of urothelial cells in BCG 10-0153 immunotherapy for superficial bladder cancer. Br J Cancer (2004) 91:607–12. 85. Ott PA, Hodi FS, Buchbinder EI. Inhibition of immune checkpoints doi: 10.1038/sj.bjc.6602026 and vascular endothelial growth factor as combination therapy for 68. Jahrsdörfer B, Hartmann G, Racila E, Jackson W, Mühlenhoff L, Meinhardt metastatic melanoma: an overview of rationale, preclinical evidence, and G, et al. CpG DNA increases primary malignant B cell expression of initial clinical data. Front Oncol (2015) 5:202. doi: 10.3389/fonc.2015. costimulatory molecules and target antigens. J Leukoc Biol. (2001) 69:81–8. 00202 doi: 10.1189/jlb.69.1.81 86. Lasek W, Zagoz˙dz˙on R, Jakobisiak M. Interleukin 12: still a promising 69. Smits ELJM, Cools N, Lion E, Van Camp K, Ponsaerts P, Berneman ZN, candidate for tumor immunotherapy? Cancer Immunol Immunother. (2014) et al. The Toll-like receptor 7/8 agonist resiquimod greatly increases the 63:419–35. doi: 10.1007/s00262-014-1523-1 immunostimulatory capacity of human acute myeloid leukemia cells. Cancer 87. Klein C, Waldhauer I, Nicolini VG, Freimoser-Grundschober A, Nayak Immunol Immunother. (2010) 59:35–46. doi: 10.1007/s00262-009-0721-8 T, Vugts DJ, et al. Cergutuzumab amunaleukin (CEA-IL2v), a CEA- 70. Pradere JP, Dapito DH, Schwabe RF. The Yin and Yang of toll-like receptors targeted IL-2 variant-based immunocytokine for combination cancer in cancer. Oncogene (2014) 33:3485–95. doi: 10.1038/onc.2013.302 immunotherapy: overcoming limitations of aldesleukin and conventional 71. Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani IL-2-based immunocytokines. Oncoimmunology (2017) 6:e1277306. RH, et al. In situ vaccination with a TLR9 agonist induces systemic doi: 10.1080/2162402X.2016.1277306 lymphoma regression: a phase I/II study. J Clin Oncol. (2010) 28:4324–32. 88. Matsuda T, Leisegang M, Park JH, Ren L, Kato T, Ikeda Y, et al. Induction doi: 10.1200/JCO.2010.28.9793 of neoantigen-specific cytotoxic t cells and construction of T-cell receptor- 72. Safety and Efficacy of MIW815 (ADU-S100) +/- Ipilimumab in Patients engineered T cells for ovarian cancer. Clin Cancer Res. (2018) 24:5357–67. With Advanced/Metastatic Solid Tumors or Lymphomas - Full Text View doi: 10.1158/1078-0432.CCR-18-0142 - ClinicalTrials.gov. Available online at: https://clinicaltrials.gov/ct2/show/ 89. Doherty M, Leighl NB, Feld R, Bradbury PA, Wang L, Nie NCT02675439 (Accessed May 25, 2018). J, et al. Phase I/II study of tumor-infiltrating lymphocyte 73. Khong A, Nelson DJ, Nowak AK, Lake RA, Robinson BWS. (TIL) infusion and low-dose interleukin-2 (IL-2) in patients The use of agonistic anti-CD40 therapy in treatments for cancer. with advanced malignant pleural mesothelioma (MPM). J Clin Int Rev Immunol. (2012) 31:246–66. doi: 10.3109/08830185.2012. Oncol. (2015) 33:TPS7586. doi: 10.1200/jco.2015.33.15_suppl.tps 698338 7586 Frontiers in Immunology | www.frontiersin.org 9 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy 90. Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain Conflict of Interest Statement: SD is also an employee for Cellectis and reports is sufficient to couple to receptor-associated signal transduction pathways. Cell personal fees from AstraZeneca, Elsalys, Erytech Pharma, and Netris Pharma. (1991) 64:891–901. 91. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, The remaining authors declare that the research was conducted in the absence of et al. Control of large, established tumor xenografts with genetically retargeted any commercial or financial relationships that could be construed as a potential human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA. conflict of interest. (2009) 106:3360–5. doi: 10.1073/pnas.0813101106 92. Research AA for C. CAR T-cell therapies produce durable remissions. Cancer Copyright © 2019 Bonaventura, Shekarian, Alcazer, Valladeau-Guilemond, Discov. (2018) 8:379. doi: 10.1158/2159-8290.CD-NB2018-017 Valsesia-Wittmann, Amigorena, Caux and Depil. This is an open-access article 93. Fesnak AD, June CH, Levine BL. Engineered T cells: the promise and distributed under the terms of the Creative Commons Attribution License (CC BY). challenges of cancer immunotherapy. Nat Rev Cancer (2016) 16:566–81. The use, distribution or reproduction in other forums is permitted, provided the doi: 10.1038/nrc.2016.97 original author(s) and the copyright owner(s) are credited and that the original 94. Kontermann RE, Brinkmann U. Bispecific antibodies. Drug publication in this journal is cited, in accordance with accepted academic practice. Discov Today (2015) 20:838–47. doi: 10.1016/j.drudis.2015. No use, distribution or reproduction is permitted which does not comply with these 02.008 terms. 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Cold Tumors: A Therapeutic Challenge for Immunotherapy

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Copyright © 2019 Bonaventura, Shekarian, Alcazer, Valladeau-Guilemond, Valsesia-Wittmann, Amigorena, Caux and Depil.
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Abstract

REVIEW published: 08 February 2019 doi: 10.3389/fimmu.2019.00168 Cold Tumors: A Therapeutic Challenge for Immunotherapy 1,2 1,2 1,2 2 Paola Bonaventura , Tala Shekarian , Vincent Alcazer , Jenny Valladeau-Guilemond , 1,2 3 1,2 Sandrine Valsesia-Wittmann , Sebastian Amigorena , Christophe Caux and 1,2,4 Stéphane Depil * 1 2 Centre Léon Bérard, Lyon, France, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France, 3 4 Institut Curie, PSL Research University, INSERM, U932, Paris, France, Université Claude Bernard Lyon 1, Lyon, France Therapeutic monoclonal antibodies targeting immune checkpoints (ICPs) have changed the treatment landscape of many tumors. However, response rate remains relatively low in most cases. A major factor involved in initial resistance to ICP inhibitors is the lack or paucity of tumor T cell infiltration, characterizing the so-called “cold tumors.” In this review, we describe the main mechanisms involved in the absence of T cell infiltration, including lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of homing into the tumor bed. We discuss then the different therapeutic approaches that could turn cold into hot tumors. In this way, specific therapies are proposed according to their mechanism of action. In addition, ‘‘supra-physiological’’ therapies, such as T cell recruiting bispecific antibodies and Edited by: Salem Chouaib, Chimeric Antigen Receptor (CAR) T cells, may be active regardless of the mechanism Institut Gustave Roussy, France involved, especially in MHC class I negative tumors. The determination of the main factors Reviewed by: implicated in the lack of preexisting tumor T cell infiltration is crucial for the development Viktor Umansky, of adapted algorithms of treatments for cold tumors. German Cancer Research Center (DKFZ), Germany Keywords: cold tumors, T cells, tumor antigen, presentation, priming, trafficking, immunotherapy Daniel Olive, Aix Marseille Université, France *Correspondence: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of many tumors, Stéphane Depil inducing durable responses in some cases, Tumor mutational load, CD8 T cell density and stephane.depil@lyon.unicancer.fr Programmed cell Death Ligand−1 (PD-L1) expression have each been proposed as distinct biomarkers of response to PD-1/-L1 antagonists. The lymphocyte infiltration and IFN-γ status Specialty section: may be key factors for effective anti-PD-1/-L1 therapy by defining a “T cell inflamed” phenotype This article was submitted to (“hot tumors”). In contrast, lack of T cells infiltrating the tumor characterizes “non-inflamed” or Cancer Immunity and Immunotherapy, a section of the journal “cold tumors” (in which other immune populations or myeloid cells can however be observed). Frontiers in Immunology Immunological treatment of cold tumors is a great challenge as no adaptive immune response has been set up or maintained. In this review, we discuss the possible issues that the immune system Received: 04 December 2018 Accepted: 21 January 2019 could encounter at different steps of the anti-tumor immune cycle (1), leading to the absence of T Published: 08 February 2019 cell infiltration: lack of tumor antigens, defect in Antigen Presenting Cells (APCs), absence of T cell activation and deficit of homing into the tumor bed (Figure 1). The potential therapeutic strategies Citation: Bonaventura P, Shekarian T, Alcazer V, to overcome these problems will be described in the second part of this review. We will not discuss Valladeau-Guilemond J, here the mechanisms of immune escape developed by inflamed tumors, reviewed elsewhere (2). Valsesia-Wittmann S, Amigorena S, Caux C and Depil S (2019) Cold LACK OF TUMOR ANTIGENS Tumors: A Therapeutic Challenge for Immunotherapy. Tumor antigens can be divided into three main classes: tumor specific antigens (TSA), cancer- Front. Immunol. 10:168. doi: 10.3389/fimmu.2019.00168 germline antigens (CGA), and tumor associated antigens (TAA) (3). TSA are expressed only by Frontiers in Immunology | www.frontiersin.org 1 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy cancer cells and not in healthy tissues (4). TSA include mutation- release, associated with different modalities of spontaneous or associated neoantigens (MANA) and viral antigens. MANAs arise induced cancer cell death, may also influence the quality of the from DNA mutation/rearrangement in a gene coding sequence T cell response (13). and play a crucial role in the recognition of tumor cells by CD8 T cells after immune checkpoint treatment (5). Viral antigens ABSENCE OF T CELL may also represent the target for immune recognition of virus- PRIMING/ACTIVATION associated tumors (6). CGA are expressed in tumor cells of different histological origins, but they are silent in normal adult Defective Recruitment of APCs tissues, except in the male germ line and trophoblastic cells The second step of the anti-tumor immune response consists (7). Their expression is associated to the demethylation of their in the presentation of tumor antigens by dendritic cells (DCs), promoter. TAA correspond to antigens with low expression in resulting in the priming and activation of specific effector T normal tissues and overexpressed in tumor cells, like HER2 (8), cells. Several DCs subsets such as classical DCs (type 1 cDC1s or melanocyte differentiation proteins (9). and type 2 cDC2s), Langerhans cells, inflammatory DCs and Tumor mutation burden (TMB) is a quantitative measure plasmacytoid DCs (pDCs) exist and are specialized in different of the total number of mutations per coding area of a tumor functions to shape the immune response and cope with the threat genome that has been shown to predict responses to ICIs in of diversity (14). In particular some evidences exist showing a range of advanced cancers (10). Tumors with a high TMB that a higher ratio of cDC1s over monocytes/macrophages in are believed to express more MANA. Interestingly, a correlation the tumor bed favors protective anti-tumoral adaptive immune between MANA and CGA has been observed (11). However, responses (15). Spranger et al. have also shown in melanoma that even if some tumors are characterized by low expression of both MHC expression and DCs infiltration is associated with T cell MANA and CGA, the quantity of tumor neoantigens does not infiltration (12). seem to be the main limiting factor for the induction of a T cell Among DCs, cDC1s excel at inducing anti-tumoral CD8 T response. A recent study by Spranger et al. analyzed the impact cell responses through cross-presentation of exogenous antigens of the presence of differentiation antigens, CGA and MANA on MHC-I (16–18). A strong correlation between CD8 gene on T cell infiltration in malignant melanoma. They reported transcript and cDC1s markers was observed, suggesting that lack that non-T-cell-inflamed melanomas do not lack antigens for of T cell activation and infiltration in the non-T-cell-inflamed T-cell recognition, arguing for other mechanisms causing the tumor microenvironment is mainly associated with a defective lack of T cell priming and recruitment. Moreover, the number recruitment and activation of cDC1 (19–21). Moreover, recent of neoantigens and the mutational load was still comparable papers published by M. Krummel and C. Reis e Sousa teams between non-T cell-inflamed and T cell-inflamed subtypes in recently demonstrated a critical role of the cross-talk between other solid tumors (12). Finally, the kinetics of tumor antigens cDC1s and NK cells for the CTL infiltration in melanoma FIGURE 1 | Reversing a cold into a hot tumor. Adapted from Chen and Mellman (1). The absence of T cells in the tumor can be due to the lack of tumor antigens, APC deficit, absence of T cell priming/activation and impaired trafficking of T cells to the tumor mass (left panel). Understanding which step of the anti-cancer immune response is not functional in cancers is crucial to adapt therapies to the cancer phenotype. Frontiers in Immunology | www.frontiersin.org 2 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy (22, 23). In mice, several reports have shown that cDC1s are in melanoma. Using a genetically engineered mouse model necessary for the natural rejection of transplanted tumors and for they showed that melanomas arising from mice with active β- the efficiency of anti-tumoral immunotherapies including ICIs or catenin were characterized by an almost complete absence of adoptive transfer of anti-tumoral CD8 T cells (24). both CD8+ T cells and cDC1 subsets (37). A second pathway identified to play a role in T cell exclusion is PI3K pathway activation/PTEN loss. Loss of PTEN in tumor cells in preclinical Lack of T Cell Co-stimulation and models of melanoma was shown to increase the expression of Activation After Antigen Presentation immunosuppressive cytokines, inhibit T cell-mediated tumor The maturation and activation of antigen-presenting DCs is killing and decrease T cell trafficking into tumors. Furthermore, a critical step for activating an efficient T cell-response. In in patients PTEN loss correlated with decreased T cell infiltration this context, the DC activation marker DC-LAMP is a good at tumor sites and inferior outcome after PD-1 inhibitor prognostic marker in solid tumors (25). Naive T cells require therapy (13). PTEN-deficient prostate tumors similarly induce an contact with activated APCs to be primed in an appropriate immunosuppressive tumor microenvironment by upregulating context of “danger signal” (26). APCs expressing Pattern PTPN11/SHP2 and inducing activity of the Jak2-Stat3 pathway Recognition Receptors (PRRs) can be directly activated by (38). Loss of PTEN was recently associated with resistance to Pathogen-Associated Molecular Patterns (PAMPs) or Danger anti-PD1 therapy in metastatic uterine leiomyosarcoma (39) and Associated Molecular Patterns (DAMPs) to become competent to the blockade of this pathway in vivo contributed to an improved prime T cell responses (27). Engagement of PRRs on DCs induces tumor control (13). NF-κB activation, up-regulation of co-stimulatory molecules, Tauriello et al. investigated how genetic alterations and production of cytokines and promotion of cross-priming (28, the tumor microenvironment (TME) interact in a metastatic 29). Various DAMPs are produced by tumor cells undergoing colorectal carcinoma (CRC) model. A Tumor Growth Factor immunological cell death [e.g., calreticulin, HighMobility Group (TGF)-β activity correlating with T cell exclusion and a low Box 1 protein (HMGB1) or Sin3A Associated Protein 130 TMB was described (40). Recently, a study associated a TGF-β (SAP130)] (30). The absence or low production of DAMPs signature of stromal cells with lack of response to anti PD-L1 in could induce a lack of DCs maturation as well as production of the excluded tumor–immune phenotype (41). Blockade of TGF-β immunosuppressive factors such as transforming growth factor in a pancreatic ductal adenocarcinoma model improved the cure beta (TGF-β) leading to the absence of CD4 T cell help (30, 31). rate of mice by decreasing the presence of immune suppressive Recent works demonstrate the importance of the protein Formyl cells in the TME and enhancing CD8+ T cell infiltration within Peptide Receptor 1 (FPR1) expressed by tumoral DCs in the the tumor (42). anthracycline-induced immunogenic cell death. DCs lacking or presenting a variant of FRP1, failed in antigen presentation and activation of T cells, resulting in poor anticancer immune Modified Production of Chemokines and responses and reduced overall survival in breast and colon Cytokines Affecting Cell Trafficking and cancer (32). Activation Stimulation of CD40 on APCs through CD40L expressed on Cytokines and chemokines may influence cell trafficking to the helper CD4+ T cells is another crucial step for the activation of tumor bed. Besides the steady-state influx of immature dendritic APCs to prime CD8 T cells. Moreover, the stimulation of CD40 cells (iDCs) within tissues, chemokines, abundantly secreted on DCs regulates the expression of the co-stimulatory molecules under inflammatory conditions, can provoke influx of iDCs in CD80 and CD86, enhances the production of cytokines (most the tumor bed (43). Lack of those chemokines and the consequent notably IL-12 and IFN-I) and promotes the cross-priming to + reduced influx of iDCs in the tumor bed can be the cause of the exogenous antigens (33). As a consequence, reduced CD8 T cell reduced activation and migration of T cells at the tumor site. responses are largely due to impaired activation of APCs or to the Chemokines acting on iDCs are the Monocyte Chemoattractant absence of co-stimulation. Proteins (CCL2, CCL7, CCL8) as well as CCL3/MIP-1alpha, CCL5/RANTES, and CCL4/MIP-1beta (44). Cytokines are also DEFICIT OF HOMING TO THE TUMOR BED necessary to generate active DCs: as an example type I interferon (IFN-I) produced by DCs can act in an autocrine manner to CD8 T Cell Exclusion by the generate fully active DC1s (45). Moreover, DC1s are a source of Immunosuppressive Peritumoral Stroma CXCL-9/10 and their absence lead to a reduced production of and Tumor Cell Alterations these chemokines (20). The chemokine CXCL16, produced by When DCs are mature and T-cells correctly primed and activated, DCs, and its receptor CXCR6 for example have been associated + + the access of T cell to the tumor bed could be compromised by the with an increased CD4 and CD8 T cell recruitment and a good stromal compartment (34). The exclusion of CD8 T cells from prognosis in CRC (46). The disruption of the CXCL16/CXCR6 the vicinity of cancer cells was shown to correlate with a poor pathway could lead to a reduced tumor T cell infiltration. long-term clinical outcome in colorectal cancer, ovarian cancer The deregulation of trafficking can directly involve T cells: and pancreatic ductal adenocarcinoma (35, 36). Interestingly, DCs-activated T cells against tumor antigens have to reach Spranger et al. reported an inverse relationship between intrinsic the tumor bed to perform their anti-cancer activity. Tumors β-catenin signaling of tumor cells and intra-tumoral T cells can disrupt chemokine expression to deregulate the immune Frontiers in Immunology | www.frontiersin.org 3 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy response and chemokines involved in effector T-cell recruitment of Th1-type chemokines in tumor cells, which is negatively + + is significantly reduced in tumors lacking a CD8 T-cell infiltrate. associated with CD8 T cells in tumors and patient outcome (48). CXCL9 and CXCL10 (CXCL11 in humans) are key chemokines There is thus a strong rationale to combine epigenetic therapy in the recruitment of CD8+ T cells engaging the CXCR3 on and immunotherapy and many clinical trials are currently their surface and their production is generally deregulated in ongoing (55). “non-inflamed” tumors (47). CXCL9/10 can be produced by the tumor cell itself where a methylation of chemokine genetic NK Cell-Based Approaches loci results in a reduced CD8 T cell infiltration. The use Natural killer (NK) cells are lymphocytes of the innate immune of demethylating agents restores chemokine production and system able to recognize and kill tumors lacking self-MHC T-cell recruitment, showing that epigenetic modification is a class I molecules, by recognizing stressed cells. For this reason mechanism of tumor escape which could lead to the lack NK approaches could be suitable in the absence of tumor of immune cells infiltration (48). Tumors can also alter the antigens or in case of deficient antigen presentation machinery chemistry of certain chemokines to preferentially recruit myeloid (e.g., lack of MHC class I). While a large portion of cancer cells: as an example the nitrosylated CCL2 eliminates the ability immunotherapies focus on targeting T cells, NK cell system to recruit CTLs and Th1 effector cells (49), while selectively for therapeutic intervention stays relatively underexplored. Nevertheless, different NK cell-based approaches have been recruiting myeloid dendritic stem cells (MDSCs) to tumor sites. described, such as ex vivo activated NK cells or NK cells transduced with a chimeric antigen receptor (CAR) to target THERAPEUTIC APPROACHES specific cancer cell surface antigen (56, 57). Antibodies-mediated targeting of NK activating receptors such as NKG2D and NKP46, Different therapeutic approaches can theoretically be used to or inhibitory receptors such as KIR and NKG2a, is under overcome the absence of T cell infiltration in tumors. These deep investigation (58). Lirilumab is a fully human antibody strategies are summarized in Figure 2. The demonstration that directed against KIR2DL-1,-2,-3 inhibitory receptors expressed these therapies can effectively transform a cold into hot tumor predominantly on NK cells and is being tested in combination remains to be done in the clinic in most instances. with ipilimumab or nivolumab for the treatment of patients bearing advanced solid malignancies (59). Specific Therapies for Tumors Expressing Few Antigens Specific Therapies for Tumors With Demethylating Agents Defective Priming or T Cell Activation It has been shown that DNA methyltransferase inhibitors Chemo/Radiotherapy Inducing Immunogenic Cell (DNMTi) and histone deacetylase inhibitors can enhance the expression of tumor antigens and components of antigen Death (ICD) processing and presenting machinery pathways, as well as other Several chemotherapies were found to work mainly in immune related genes (50, 51). These agents can also induce immunocompetent subjects, accumulating evidences that tumor the expression of retroelements such as endogenous retroviruses inhibition partially relies on the immune system competence (ERVs), usually silent and able to induce a type I IFN response and not only on the direct anti-tumor toxicity of chemotherapy (52). Epigenetic drugs have been reported to induce transcription (60). In this regard ICD inducing chemotherapeutic agents from normally repressed ERV LTR, that may cause ectopic can be classified within cancer immunotherapy strategies. expression of transcripts with canonical or novel open reading Radiotherapy was initially designed to selectively kill tumor frames, leading to the production of immunogenic peptides cells within the irradiated field. However, emerging evidence (53, 54). DNMTi and Histone-lysine N-methyltransferase EZH2 indicates that radiotherapy, by inducing ICD, harnesses the inhibitors have also been shown to reverse epigenetic silencing host’s immune system to attack the tumor cells outside the FIGURE 2 | Specific and common approaches to overcome the absence of T cells in tumors. According to the mechanism involved in the lack of T cell infiltration in tumors, specific therapies can be selected. In the case of MHC-I negative tumors or if specific therapies are not sufficient, “supra-physiological therapies” can be used. Frontiers in Immunology | www.frontiersin.org 4 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy irradiation field, explaining the “abscopal” effect (regression of to activate and “license” DCs to prime effective cytotoxic CD8 tumor lesions outside the irradiation field) (61). Based on this T cell responses. CD40 signaling can also be effectively triggered rationale, many trials are ongoing to combine chemotherapy using agonistic antibodies or CD40L, thus bypassing the need and radiotherapy with PD-1/PD-L1 antibodies. Of note, for CD4 helper T cells (73). In preclinical studies, agonistic the same rationale also applies to antibody-drug conjugates CD40 antibodies have demonstrated T cell-dependent anti- (ADCs) with cytotoxic payloads capable of inducing ICD, tumor activity, in particular in combination with conventional justifying the initiation of clinical trials combining ADCs and chemotherapy and immune checkpoint inhibitors (ICIs). Many immunotherapy (62). CD40 antibodies are under clinical development (74). Toxicity profile is acceptable in monotherapy and combination trials are Oncolytic Viruses ongoing (75). Oncolytic viruses are common viruses that can selectively target, Tumor Vaccines replicate in and destroy cancer cells (63). Most oncolytic viruses The therapeutic breakthrough provided by ICIs and the can induce cancer cell death and directly eliminate tumor demonstration of the role of MANA in T-cell mediated cells, but they also initiate systemic immune responses through antitumor response have paved the way for a next generation different mechanisms such as induction of ICD and release of personalized cancer vaccines based on the use of MANA of danger signals (DAMPs) and tumor antigens from virus- specific of the tumor. Preclinical results showed induction of infected cells. They also release viral PAMPs contributing to efficient antitumor response and clinical trials providing a clinical APCs maturation that conduct to activation of antigen-specific + + proof of concept in melanoma have been published (76–78). A CD4 and CD8 T cell responses (64). Moreover, the infected + + specific CD8 and CD4 T cell immune response characterized cells are directly recognized by the innate immune system by the induction or the amplification of a preexisting response such as NK cells or macrophages (65). It has been recently against MANA has been shown. Encouraging clinical activity shown in a melanoma phase I trial that use of oncolytic seems to be associated but larger trials are awaited to firmly viro-therapy was able to convert a cold into hot tumor, as demonstrate the clinical activity of this therapeutic approach. patients with a low level of immune cell infiltrate and a Theoretically, cancer vaccines may either reinforce the activity negative IFNγ signature before treatment responded well to and therapeutic margin of ICIs by increasing the number of the combination of talimogene laherparepvec with the PD-1 specific effector T cells, or convert cold into inflamed tumors. antagonist pembrolizumab (66). The potential limitations are the availability of T cell repertoire in cancer patients and the risk of specific loss of heterozygosity PRR Agonists (LOH) of the HLA presenting MANA in advanced metastatic PRRs consist of five families including Toll-like receptors (TLRs), tumors (79). RIG-I-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors Specific Therapies for Tumors With (CLRs), and cytoplasmic DNA sensors. PRRs agonists have notably the ability to activate PRR pathways inducing antigen Impaired T Cell Trafficking to the Tumor presentation by myeloid cells residing in the tumor micro- TGF-β Blocking Antibodies and TGF-β-Receptor environment (67–69). Antagonists TLR agonists showed controversial results in pre-clinical TGF-β has been involved in cell proliferation, angiogenesis, studies by either promoting or inhibiting tumor progression epithelial-to-mesenchymal transition, immune infiltration, depending on the TLR and the tumor type (70). Multiple TLR metastases dissemination, and drug resistance (80). Of note agonists are currently in clinical development. As an example, TGF-β produced by the tumor cells mediates alterations in the intra-tumoral injections of a TLR-9 agonist, the CpG-rich tumor-associated pDCs functions, e.g., impaired capacity to oligonucleotide PF-3512676, showed significant activity in both produce IFN type I, leading to a lacking/unbalanced T cell injected and non-injected lesions of B- and T-cell lymphomas recruitment (81, 82). Recent reports have shown that TGF- when used concomitantly with low-dose (2 × 2 Gy) local β in the peritumoral area was a major factor involved in irradiation (71). T cell exclusion from the tumor. Mariathasan et al. used a STING has been shown to play an important role in the innate preclinical model recapitulating T cell exclusion and showed immune response against cancer. In the TME, tumor cell DNA that combination of a TGFβ blocking antibody with a PD-L1 detected by APCs is correlated with activation of STING pathway antibody induced T cell penetration into the center of tumors, that leads to IFN-β production (25), enhancing CD8 T cell allowing anti-tumor immunity and tumor regression (41). priming and trafficking of effector T cells. One STING agonist, Several TGF-β antibodies or small molecules TGF-β-receptor ADU-S100 (Aduro Biotech/Novartis), is currently evaluated antagonists are in clinical development and could be tested in in phase I clinical trial by intra-tumoral administration in this setting. cutaneously accessible tumors (72). Anti-angiogenic Therapies CD 40 Agonistic Antibodies The clinical activity of anti-angiogenic drugs is modest when CD40 is broadly expressed on immune cells, predominantly on used as single agent. However, it has been shown that DCs, B cells and macrophages. A major role of CD40 signaling is anti-angiogenic drugs normalize the tumor vasculature and Frontiers in Immunology | www.frontiersin.org 5 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy induce the upregulation of the leukocyte adhesion molecules demonstrate and will probably require optimization of CAR ICAM-1 and VCAM-1 on tumor endothelial cells (83), leading functions [for review see (93)]. to increased T cell infiltration (84). These therapies may thus T-Cell Recruiting Bi-specific Antibodies represent a treatment of choice for tumors characterized by T Bi-specific antibodies (bsAbs) are engineered antibodies that cells blocked in the periphery of the tumor in order to enhance can bind two different antigens. One of the main strategies in intratumoral penetration of T cells. It has been shown in the the development of bsAbs is the recruitment and activation of clinic that anti-angiogenic therapies could synergize with ICIs in immune effector T cells by targeting CD3 domain of the TCR metastatic melanoma (85). complex (T-cell recruiting bsAbs) together with another antigen abnormally expressed on the tumor cell surface. The approval of Immunocytokines catumaxomab (anti-epitelial cell adhesion molecule EpCAM and Cytokines such as IL-2, TNF, IL-12 mediate the influx and anti-CD3) and blinatumomab (anti-CD19 and anti-CD3) has expansion of leukocytes at the tumor site. However, these become a major milestone in the development of bsAbs. BsAbs cytokines, and especially IL-12, induce significant toxicity when can be divided into two categories: immunoglobulin G (IgG)- administrated systemically in clinical trials (86). Next generation like molecules and non-IgG-like molecules. Non-IgG-like bsAbs immunocytokines combining a fragment from a specific tumor are smaller in size, leading to enhanced tissue penetration, but antigen antibody with a modified cytokine are being developed shorter half-life (94). Currently, more than 60 different bsAbs with the aim of activating specifically the immune system formats exist, some of them making their way into clinical inside the tumor to reduce systemic side effects. For example, trials. As for CAR T-cells, activity of T cell-recruiting bsAbs is cergutuzumab amunaleukin (CEA-IL2v), is a novel monomeric not dependent on MHC class I expression on tumor cells and CEA-targeted immunocytokine that comprises a single IL- both approaches represent thus very promising treatments for 2 variant (IL2v) moiety with abolished CD25 binding (to MHC I-negative cold tumors. It is however not know whether avoid activation of regulatory T cells) fused to the C-terminus a minimum threshold of T cells inside the tumor is required for of a high affinity bivalent carcinoembryonic antigen (CEA)- the activity of bsAb, alone or in combination with other therapies. specific antibody devoid of Fc-mediated effector functions. A comparison between CAR T cells and T-cell recruiting bsAbs A superior efficacy over the respecting monotherapies was is proposed in Table 1. observed with CEA-IL-2v in combination with PD-L1 antibody and ADCC competent antibodies in CEA-positive solid tumor models (87). PERSPECTIVES Changing the natural history of a tumor characterized by Therapeutic Approaches Active in Different the absence of T cells remains a great therapeutic challenge. Immune Contexts However, as discussed above, many therapeutic approaches can Adoptive T Cell Therapy and Chimeric Antigen be evaluated in this context. A major issue will be to determine Receptor (CAR) T Cells the origin of this lack of T cell response to adapt the therapy to the Historically, cell-based therapies have focused on cytotoxic T physiology of the tumor. Figure 2 summarizes the possibilities of cells targeting MHC-restricted antigens. This approach remains treatment according to this tumor context. promising, in particular with the development of T cell Conventional anticancer approaches like chemotherapy receptor (TCR)-engineered T cells (88) and improvement of and radiotherapy have still a room in the therapeutic tumor infiltrating lymphocytes (TILs) infusion (89). However, armamentarium, not only to potentially induce ICD but their efficacy may be limited by the tendency of tumors to also to reduce the tumor burden and thus potentially decrease downregulate MHC molecules. CARs are engineered receptors the selection of immune-resistant clones. In other cases, “in made of the combination of an antigen binding domain of a situ” vaccination using PRR or CD40 agonists may be used to monoclonal antibody specific for a cancer antigen (not MHC induce a specific immune antitumor response against naturally restricted) together with an intracellular domain of the CD3-zeta presented tumor antigens. Personalized cancer vaccines also chain (90). CAR T cells responses can be further enhanced by represent a very promising strategy especially in highly mutated addition of costimulatory domains, such as CD28 and CD137 tumors. Finally, “supra-physiological” approaches like CAR (4-IBB) to support the expansion and persistence of genetically T cells or T-cell recruiting bsAbs could be efficient in tumors engineered cells in vivo (91). The reinfusion of CAR T-cells is characterized by the absence of MHC expression or even LOH preceded by a “lymphodepleting” chemotherapy regimen used to of the HLA alleles presenting tumor antigens. It is likely that physically create enough space for the expansion and persistence in the near future, algorithms of treatment will be developed of CAR T cell clones. Over the past decade multiple tumor to adapt the therapeutic strategy to the immune context of antigens have been targeted by CARs. Outstanding activity of the tumor, considering also space and time evolution for CAR T cells targeting CD19 has been observed in hematological adequate sequential strategies. At the end, while the efficacy malignancies, in particular in acute lymphoblastic leukemia and of the therapy in inflamed tumors depends principally in the Diffuse Large B cell lymphoma with two CAR T-cell therapies remove of the breaks induced by the immune activation itself, approved by the Food and Drug Administration (FDA) in 2017 the conversion of a cold into an inflamed tumor will require a (92). The clinical activity of CAR in solid tumors is still to prior combination of therapies to induce immune infiltration Frontiers in Immunology | www.frontiersin.org 6 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy TABLE 1 | Comparison between CAR T-cells and T-cell recruiting bi-specific antibodies. CAR T-Cells Bi-specific antibodies Mechanism of - Direct cancer antigen recognition - Recruitment of immune effector T cells by their CD3 with another action - Non MHC-restricted antigen expressed on the tumor cell - Does not require pre-existing T cell infiltration, independent of - Non MHC-restricted receiver T cell characteristics - May be more dependent on quantity/quality of patients’ T cells Administration - Single administration - Repeated administration (continuous infusion for non-IgG-like) - Long half-life (months/years) - Short/intermediate half-life (hours/days) Tissue - Homing of the T cells for blood, lymph nodes, and bone marrow - Non IgG like: enhanced tissue penetration penetration Toxicity - Acute reversible neurotoxicity (CD19) - Lower toxicity expected - Cytokine release syndrome (CRS) - Acute reversible neurotoxicity (CD19) - Cytokine release syndrome (CRS) Main diseases - Outstanding activity in some hematological malignancies: B cell - B cell acute lymphoblastic leukemia (CD19) acute lymphoblastic leukemia, Diffuse Large B cell lymphoma - Clinical trials for many solid tumors including colorectal, ovarian, (CD19) breast and prostate cancer - Clinical trials in solid tumors Other - Clinical activity in solid tumors is still to demonstrate - Clinical activity in solid tumors is still to demonstrate limitations - Immunosuppressive microenvironment (rationale for - Immunosuppressive microenvironment (rationale for combination combination with ICIs or use of optimized CAR T-cells) with ICIs) - Target specificity: risk of escape by loss of the target - Target specificity: risk of escape by loss of the target Cost and - Long process, manufacturing issues - Immediate availability, less manufacturing and regulatory issues +++ + availability - Cost - Cost and then different immune checkpoint modulators to remove FUNDING the breaks. This work was supported by grants from Programme de Recherche Translationnelle en Cancérologie INCa-DGOS (INCa PRT-K2017-072), the Rhône comity of the Ligue AUTHOR CONTRIBUTIONS Contre le Cancer, the SIRC project (LYRICAN, INCa- PB, TS, VA, JV-G, and SD contributed to the DGOS-Inserm_12563), and the LABEX DEVweCAN writing. SD and CC contributed to the conception. (ANR-10-LABX-0061) of the University of Lyon, within SV-W, SA, CC, and SD participated in the lecture the program Investissements d’Avenir organized by the French and corrections. National Agency (ANR). REFERENCES ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med. (1995) 181: 2109–17. 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity 9. Coulie PG, Brichard V, Van Pel A, Wölfel T, Schneider J, Traversari C, et al. cycle. Immunity (2013) 39:1–10. doi: 10.1016/j.immuni.2013.07.012 A new gene coding for a differentiation antigen recognized by autologous 2. Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells cytolytic T lymphocytes on HLA-A2 melanomas. J Exp Med. (1994) 180:35– in the tumor microenvironment. Nat Immunol. (2013) 14:1014–22. 42. doi: 10.1038/ni.2703 10. Yarchoan M, Johnson BA, Lutz ER, Laheru DA, Jaffee EM. Targeting 3. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and neoantigens to augment antitumour immunity. Nat Rev Cancer (2017) response rate to PD-1 Inhibition. N Engl J Med. (2017) 377:2500–1. 17:209–222. doi: 10.1038/nrc.2016.154 doi: 10.1056/NEJMc1713444 11. Ilyas S, Yang JC. Landscape of tumor antigens in T-cell immunotherapy. J 4. Kelderman S, Kvistborg P. Tumor antigens in human cancer Immunol. (2015) 195:5117–22. doi: 10.4049/jimmunol.1501657 control. Biochim Biophys Acta BBA Rev Cancer (2016) 1865:83–9. 12. Spranger S, Luke JJ, Bao R, Zha Y, Hernandez KM, Li Y, et al. Density of doi: 10.1016/j.bbcan.2015.10.004 immunogenic antigens does not explain the presence or absence of the T-cell– 5. Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour inflamed tumor microenvironment in melanoma. Proc Natl Acad Sci USA. antigens recognized by T lymphocytes: at the core of cancer (2016) 113:E7759–68. doi: 10.1073/pnas.1609376113 immunotherapy. Nat Rev Cancer (2014) 14:135–46. doi: 10.1038/nrc 13. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of 3670 PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6. Mitch L. Mutation Burden Predicts Anti-PD-1 Response. Cancer Discov. (2016) 6:202–216. doi: 10.1158/2159-8290.CD-15-0283 (2018) 8:258. doi: 10.1158/2159-8290.CD-NB2018-005 14. Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: 7. Chomez P, De Backer O, Bertrand M, De Plaen E, Boon T, Lucas S. An ontogeny and function of dendritic cells and their subsets in the steady overview of the MAGE gene family with the identification of all human state and the inflamed setting. Annu Rev Immunol. (2013) 31:563–604. members of the family. Cancer Res. (2001) 61:5544–51. doi: 10.1146/annurev-immunol-020711-074950 8. Fisk B, Blevins TL, Wharton JT, Ioannides CG. Identification of an 15. Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, immunodominant peptide of HER-2/neu protooncogene recognized by et al. Dendritic cells, monocytes and macrophages: a unified nomenclature Frontiers in Immunology | www.frontiersin.org 7 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy based on ontogeny. Nat Rev Immunol. (2014) 14:571–8. doi: 10.1038/ high levels of self/tumor antigen-specific CD8+ T cells in patients with nri3712 melanoma. J Immunol. (2005) 175:6169–76. doi: 10.4049/jimmunol.175.9. 16. Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, 6169 et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique 35. Lohneis P, Sinn M, Bischoff S, Jühling A, Pelzer U, Wislocka L, et al. myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. Cytotoxic tumour-infiltrating T lymphocytes influence outcome in resected (2010) 207:1247–60. doi: 10.1084/jem.20092140 pancreatic ductal adenocarcinoma. Eur J Cancer (2017) 83:290–301. 17. Bachem A, Güttler S, Hartung E, Ebstein F, Schaefer M, Tannert A, et al. doi: 10.1016/j.ejca.2017.06.016 Superior antigen cross-presentation and XCR1 expression define human 36. Peranzoni E, Lemoine J, Vimeux L, Feuillet V, Barrin S, Kantari-Mimoun CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J Exp C, et al. Macrophages impede CD8 T cells from reaching tumor cells and Med. (2010) 207:1273–81. doi: 10.1084/jem.20100348 limit the efficacy of anti–PD-1 treatment. Proc Natl Acad Sci USA. (2018) 18. Fuertes MB, Kacha AK, Kline J, Woo SR, Kranz DM, Murphy KM, 115:E4041–50. doi: 10.1073/pnas.1720948115 et al. Host type I IFN signals are required for antitumor CD8+ T cell 37. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin responses through CD8α+ dendritic cells. J Exp Med. (2011) 208:2005–16. signalling prevents anti-tumour immunity. Nature (2015) 523:231–5. doi: 10.1084/jem.20101159 doi: 10.1038/nature14404 19. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, 38. Toso A, Revandkar A, Di Mitri D, Guccini I, Proietti M, Sarti M, et al. et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by cytotoxic T cell immunity. Science (2008) 322:1097–100. doi: 10.1126/science. activating the senescence-associated antitumor immunity. Cell Rep. (2014) 1164206 9:75–89. doi: 10.1016/j.celrep.2014.08.044 20. Spranger S, Dai D, Horton B, Gajewski TF. Tumor-residing Batf3 39. George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, Shukla S, dendritic cells are required for effector t cell trafficking and adoptive et al. Loss of PTEN Is Associated with resistance to Anti-PD-1 t cell therapy. Cancer Cell (2017) 31:711–23.e4. doi: 10.1016/j.ccell.2017. checkpoint blockade therapy in metastatic uterine leiomyosarcoma. 04.003 Immunity (2017) 46:197–204. doi: 10.1016/j.immuni.2017. 21. Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack 02.001 JL, Erle DJ, et al. Dissecting the tumor myeloid compartment 40. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia- reveals rare activating antigen-presenting cells critical for T cell Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically immunity. Cancer Cell (2014) 26:638–52. doi: 10.1016/j.ccell.2014. reconstituted colon cancer metastasis. Nature (2018) 554:538–43. 09.007 doi: 10.1038/nature25492 22. Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, 41. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. Sammicheli S, et al. NK cells stimulate recruitment of cDC1 into the tumor TGFβ attenuates tumour response to PD-L1 blockade by contributing to microenvironment promoting cancer immune control. Cell (2018) 172:1022– exclusion of T cells. Nature (2018) 554:544–8. doi: 10.1038/nature25501 37.e14. doi: 10.1016/j.cell.2018.01.004 42. Soares KC, Rucki AA, Kim V, Foley K, Solt S, Wolfgang CL, et al. 23. Barry KC, Hsu J, Broz ML, Cueto FJ, Binnewies M, Combes AJ, et al. A TGF-β blockade depletes T regulatory cells from metastatic pancreatic natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor tumors in a vaccine dependent manner. Oncotarget (2015) 6:43005–15. microenvironments. Nat Med. (2018) 24:1178–91. doi: 10.1038/s41591-018- doi: 10.18632/oncotarget.5656 0085-8 43. Randolph GJ, Ochando J, Partida-Sánchez S. Migration of dendritic cell 24. Sánchez-Paulete AR, Cueto FJ, Martínez-López M, Labiano S, Morales- subsets and their precursors. Annu Rev Immunol. (2008) 26:293–316. Kastresana A, Rodríguez-Ruiz ME, et al. Cancer immunotherapy with doi: 10.1146/annurev.immunol.26.021607.090254 immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies 44. Luther SA, Cyster JG. Chemokines as regulators of T cell differentiation. Nat requires BATF3-dependent dendritic cells. Cancer Discov. (2016) 6:71–9. Immunol. (2001) 2:102–7. doi: 10.1038/84205 doi: 10.1158/2159-8290.CD-15-0510 45. Montoya M, Schiavoni G, Mattei F, Gresser I, Belardelli F, Borrow P, 25. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung et al. Type I interferons produced by dendritic cells promote their MYK, et al. STING-dependent cytosolic DNA sensing mediates innate phenotypic and functional activation. Blood (2002) 99:3263–3271. immune recognition of immunogenic tumors. Immunity (2014) 41:830–42. doi: 10.1182/blood.V99.9.3263 doi: 10.1016/j.immuni.2014.10.017 46. Hojo S, Koizumi K, Tsuneyama K, Arita Y, Cui Z, Shinohara K, et al. High- 26. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez level expression of chemokine CXCL16 by tumor cells correlates with a good M, Poulot V, et al. Long-term survival for patients with non- prognosis and increased tumor-infiltrating lymphocytes in colorectal cancer. small-cell lung cancer with intratumoral lymphoid structures. Cancer Res. (2007) 67:4725–31. doi: 10.1158/0008-5472.CAN-06-3424 J Clin Oncol. (2008) 26:4410–7. doi: 10.1200/JCO.2007. 47. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff 15.0284 C, et al. Chemokine expression in melanoma metastases associated 27. Akira S, Uematsu STO. Pathogen recognition and innate immunity. Cell with CD8+ T-cell recruitment. Cancer Res. (2009) 69:3077–85. (2006) 124:783–801. doi: 10.1016/j.cell.2006.02.015 doi: 10.1158/0008-5472.CAN-08-2281 28. Janeway CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 48. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. (2002) 20:197–216. doi: 10.1146/annurev.immunol.20.083001.084359 Epigenetic silencing of TH1-type chemokines shapes tumour immunity and 29. Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol. (2006) immunotherapy. Nature (2015) 527:249–53. doi: 10.1038/nature15520 6:476–83. doi: 10.1038/nri1845 49. Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S, Avella D, et al. Chemokine 30. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell nitration prevents intratumoral infiltration of antigen-specific T cells. J Exp death in cancer therapy. Annu Rev Immunol. (2013) 31:51–72. Med. (2011) 208:1949–62. doi: 10.1084/jem.20101956 doi: 10.1146/annurev-immunol-032712-100008 50. Srivastava P, Paluch BE, Matsuzaki J, James SR, Collamat-Lai G, Karbach 31. Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic J, et al. Immunomodulatory action of SGI-110, a hypomethylating cell death. Nat Rev Immunol. (2009) 9:353–63. doi: 10.1038/nri2545 agent, in acute myeloid leukemia cells. Leuk Res. (2014) 38:1332. 32. Vacchelli E, Ma Y, Baracco EE, Sistigu A, Enot DP, Pietrocola F, doi: 10.1016/j.leukres.2014.09.001 et al. Chemotherapy-induced antitumor immunity requires formyl peptide 51. Dunn J, Rao S. Epigenetics and immunotherapy: the current state receptor 1. Science (2015) 350:972–8. doi: 10.1126/science.aad0779 of play. Mol Immunol. (2017) 87:227–39. doi: 10.1016/j.molimm.2017. 33. Ridge JP, Di Rosa FMP. A conditioned dendritic cell can be a temporal 04.012 bridge between a CD4+ T-helper and a T-killer cell. Nature (1998) 393:474–8. 52. Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, doi: 10.1038/30989 et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer 34. Rosenberg SA, Sherry RM, Morton KE, Scharfman WJ, Yang JC, Topalian via dsRNA including endogenous retroviruses. Cell (2015) 162:974–86. SL, et al. Tumor progression can occur despite the induction of very doi: 10.1016/j.cell.2015.07.011 Frontiers in Immunology | www.frontiersin.org 8 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy 53. Brocks D, Schmidt CR, Daskalakis M, Jang HS, Shah NM, Li D, et al. DNMT 74. Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, et al. Phase I and HDAC inhibitors induce cryptic transcription start sites encoded in long study of the CD40 agonist antibody CP-870,893 combined with carboplatin terminal repeats. Nat Genet. (2017) 49:1052–60. doi: 10.1038/ng.3889 and paclitaxel in patients with advanced solid tumors. Oncoimmunology 54. Licht JD. DNA Methylation inhibitors in cancer therapy: the immunity (2013) 2:e23033. doi: 10.4161/onci.23033 dimension. Cell (2015) 162:938–9. doi: 10.1016/j.cell.2015.08.005 75. Vonderheide RH. The immune revolution: a case for priming, not 55. Chiappinelli KB, Zahnow CA, Ahuja N, Baylin SB. Combining epigenetic checkpoint. Cancer Cell (2018) 33:563–9. doi: 10.1016/j.ccell.2018. and immune therapy to combat cancer. Cancer Res. (2016) 76:1683. 03.008 doi: 10.1158/0008-5472.CAN-15-2125 76. Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, et al. An immunogenic 56. Zhang C, Oberoi P, Oelsner S, Waldmann A, Lindner A, Tonn T, personal neoantigen vaccine for patients with melanoma. Nature (2017) et al. Chimeric antigen receptor-engineered NK-92 cells: an off-the- 547:217–221. doi: 10.1038/nature22991 shelf cellular therapeutic for targeted elimination of cancer cells and 77. Sahin U, Derhovanessian E, Miller M, Kloke B-P, Simon P, Löwer M, et al. induction of protective antitumor immunity. Front Immunol. (2017) 8:533. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic doi: 10.3389/fimmu.2017.00533 immunity against cancer. Nature (2017) 547:222–6. doi: 10.1038/nature 57. Chu J, Deng Y, Benson DM, He S, Hughes T, Zhang J, et al. CS1-specific 23003 chimeric antigen receptor (CAR)-engineered natural killer cells enhance 78. Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal in vitro and in vivo anti-tumor activity against human multiple myeloma. J, Petti AA, et al. Cancer immunotherapy. A dendritic cell vaccine Leukemia (2014) 28:917–27. doi: 10.1038/leu.2013.279 increases the breadth and diversity of melanoma neoantigen- 58. Mahoney KM, Rennert PD, Freeman GJ. Combination cancer specific T cells. Science (2015) 348:803–8. doi: 10.1126/science. immunotherapy and new immunomodulatory targets. Nat Rev Drug aaa3828 Discov. (2015) 14:561–84. doi: 10.1038/nrd4591 79. McGranahan N, Rosenthal R, Hiley CT, Rowan AJ, Watkins TBK, Wilson GA, 59. Aranda F, Vacchelli E, Eggermont A, Galon J, Fridman WH, Zitvogel L, et al. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Trial watch: immunostimulatory monoclonal antibodies in cancer therapy. Cell (2017) 171:1259–71.e11. doi: 10.1016/j.cell.2017.10.001 Oncoimmunology (2014) 3:e27297. doi: 10.4161/onci.27297 80. Gramont A de, Faivre S, Raymond E. Novel TGF-β inhibitors ready 60. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden for prime time in onco-immunology. Oncoimmunology (2017) 6:e1257453. SF, et al. Leukocyte complexity predicts breast cancer survival and doi: 10.1080/2162402X.2016.1257453 functionally regulates response to chemotherapy. Cancer Discov. (2011) 81. Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A, doi: 10.1158/2159-8274.CD-10-0028 et al. Quantitative and functional alterations of plasmacytoid dendritic cells 61. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin contribute to immune tolerance in ovarian cancer. Cancer Res. (2011) Radiat Oncol. (2015) 25:11–7. doi: 10.1016/j.semradonc.2014.07.005 71:5423–34. doi: 10.1158/0008-5472.CAN-11-0367 62. Parslow AC, Parakh S, Lee FT, Gan HK, Scott AM. Antibody- 82. Sisirak V, Faget J, Vey N, Blay JY, Ménétrier-Caux C, Caux C, drug conjugates for cancer therapy. Biomedicines (2016) 4:14 et al. Plasmacytoid dendritic cells deficient in IFNα production doi: 10.3390/biomedicines4030014 promote the amplification of FOXP3+ regulatory T cells 63. Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol. (2012) and are associated with poor prognosis in breast cancer 30:658–70. doi: 10.1038/nbt.2287 patients. Oncoimmunology (2013) 2:e22338: doi: 10.4161/onci. 64. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class 22338 of immunotherapy drugs. Nat Rev Drug Discov. (2015) 14:642–62. 83. Kandalaft LE, Motz GT, Busch J, Coukos G. Angiogenesis and the tumor doi: 10.1038/nrd4663 vasculature as antitumor immune modulators: the role of vascular endothelial 65. Seth RB, Sun L, Chen ZJ. Antiviral innate immunity pathways. Cell Res. (2006) growth factor and endothelin. Curr Top Microbiol Immunol. (2011) 344:129– 16:141–7. doi: 10.1038/sj.cr.7310019 48. doi: 10.1007/82_2010_95 66. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin 84. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg O, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration SA. Antiangiogenic agents can increase lymphocyte infiltration into and improves anti-PD-1 immunotherapy. Cell (2017) 170:1109–19.e10. tumor and enhance the effectiveness of adoptive immunotherapy of doi: 10.1016/j.cell.2017.08.027 cancer. Cancer Res. (2010) 70:6171–80. doi: 10.1158/0008-5472.CAN- 67. Bevers RFM, Kurth K-H, Schamhart DHJ. Role of urothelial cells in BCG 10-0153 immunotherapy for superficial bladder cancer. Br J Cancer (2004) 91:607–12. 85. Ott PA, Hodi FS, Buchbinder EI. Inhibition of immune checkpoints doi: 10.1038/sj.bjc.6602026 and vascular endothelial growth factor as combination therapy for 68. Jahrsdörfer B, Hartmann G, Racila E, Jackson W, Mühlenhoff L, Meinhardt metastatic melanoma: an overview of rationale, preclinical evidence, and G, et al. CpG DNA increases primary malignant B cell expression of initial clinical data. Front Oncol (2015) 5:202. doi: 10.3389/fonc.2015. costimulatory molecules and target antigens. J Leukoc Biol. (2001) 69:81–8. 00202 doi: 10.1189/jlb.69.1.81 86. Lasek W, Zagoz˙dz˙on R, Jakobisiak M. Interleukin 12: still a promising 69. Smits ELJM, Cools N, Lion E, Van Camp K, Ponsaerts P, Berneman ZN, candidate for tumor immunotherapy? Cancer Immunol Immunother. (2014) et al. The Toll-like receptor 7/8 agonist resiquimod greatly increases the 63:419–35. doi: 10.1007/s00262-014-1523-1 immunostimulatory capacity of human acute myeloid leukemia cells. Cancer 87. Klein C, Waldhauer I, Nicolini VG, Freimoser-Grundschober A, Nayak Immunol Immunother. (2010) 59:35–46. doi: 10.1007/s00262-009-0721-8 T, Vugts DJ, et al. Cergutuzumab amunaleukin (CEA-IL2v), a CEA- 70. Pradere JP, Dapito DH, Schwabe RF. The Yin and Yang of toll-like receptors targeted IL-2 variant-based immunocytokine for combination cancer in cancer. Oncogene (2014) 33:3485–95. doi: 10.1038/onc.2013.302 immunotherapy: overcoming limitations of aldesleukin and conventional 71. Brody JD, Ai WZ, Czerwinski DK, Torchia JA, Levy M, Advani IL-2-based immunocytokines. Oncoimmunology (2017) 6:e1277306. RH, et al. In situ vaccination with a TLR9 agonist induces systemic doi: 10.1080/2162402X.2016.1277306 lymphoma regression: a phase I/II study. J Clin Oncol. (2010) 28:4324–32. 88. Matsuda T, Leisegang M, Park JH, Ren L, Kato T, Ikeda Y, et al. Induction doi: 10.1200/JCO.2010.28.9793 of neoantigen-specific cytotoxic t cells and construction of T-cell receptor- 72. Safety and Efficacy of MIW815 (ADU-S100) +/- Ipilimumab in Patients engineered T cells for ovarian cancer. Clin Cancer Res. (2018) 24:5357–67. With Advanced/Metastatic Solid Tumors or Lymphomas - Full Text View doi: 10.1158/1078-0432.CCR-18-0142 - ClinicalTrials.gov. Available online at: https://clinicaltrials.gov/ct2/show/ 89. Doherty M, Leighl NB, Feld R, Bradbury PA, Wang L, Nie NCT02675439 (Accessed May 25, 2018). J, et al. Phase I/II study of tumor-infiltrating lymphocyte 73. Khong A, Nelson DJ, Nowak AK, Lake RA, Robinson BWS. (TIL) infusion and low-dose interleukin-2 (IL-2) in patients The use of agonistic anti-CD40 therapy in treatments for cancer. with advanced malignant pleural mesothelioma (MPM). J Clin Int Rev Immunol. (2012) 31:246–66. doi: 10.3109/08830185.2012. Oncol. (2015) 33:TPS7586. doi: 10.1200/jco.2015.33.15_suppl.tps 698338 7586 Frontiers in Immunology | www.frontiersin.org 9 February 2019 | Volume 10 | Article 168 Bonaventura et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy 90. Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain Conflict of Interest Statement: SD is also an employee for Cellectis and reports is sufficient to couple to receptor-associated signal transduction pathways. Cell personal fees from AstraZeneca, Elsalys, Erytech Pharma, and Netris Pharma. (1991) 64:891–901. 91. Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, The remaining authors declare that the research was conducted in the absence of et al. Control of large, established tumor xenografts with genetically retargeted any commercial or financial relationships that could be construed as a potential human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA. conflict of interest. (2009) 106:3360–5. doi: 10.1073/pnas.0813101106 92. Research AA for C. CAR T-cell therapies produce durable remissions. Cancer Copyright © 2019 Bonaventura, Shekarian, Alcazer, Valladeau-Guilemond, Discov. (2018) 8:379. doi: 10.1158/2159-8290.CD-NB2018-017 Valsesia-Wittmann, Amigorena, Caux and Depil. This is an open-access article 93. Fesnak AD, June CH, Levine BL. Engineered T cells: the promise and distributed under the terms of the Creative Commons Attribution License (CC BY). challenges of cancer immunotherapy. Nat Rev Cancer (2016) 16:566–81. The use, distribution or reproduction in other forums is permitted, provided the doi: 10.1038/nrc.2016.97 original author(s) and the copyright owner(s) are credited and that the original 94. Kontermann RE, Brinkmann U. Bispecific antibodies. Drug publication in this journal is cited, in accordance with accepted academic practice. Discov Today (2015) 20:838–47. doi: 10.1016/j.drudis.2015. No use, distribution or reproduction is permitted which does not comply with these 02.008 terms. 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