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Hodgkin’s lymphoma (HL) is characterized by a high background of inflammatory cells which play an important role for the pathogenesis of the disease. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory immune checkpoint receptor and a putative target for novel immunotherapies. To study patterns of TIGIT expression in the T cell background surrounding malignant cells including Hodgkin cells, Reed-Sternberg cells and histiocytic cells, a microenvironment (ME) tissue microarray (TMA) was constructed from tissue punches measuring 2 mm in diameter obtained from formalin-fixed tissue samples of Hodgkin’s lymphoma lymph nodes (n = 40) and normal human tonsil (n = 2). The ME-TMA was stained by brightfield and fluorescence multiplex immunohistochemistry (IHC) to evaluate expression levels of TIGIT and PD-1 as well as standard lymphocyte markers (CD3, CD8, CD4, FOXP3) in the lymphocytic background. All analyzed cases of HL contained 9–99% (median: 86%) of TIGIT lymphoid cells. In general, TIGIT localized to the same cells as PD-1. Strikingly, expression levels of TIGIT and PD-1 were highly variable among the analyzed samples. Highest levels of TIGIT and PD-1 were found in one sample of nodular lymphocytic-predominant HL (NLPHL). In conclusion, TIGIT expression is highly variable between patients with Hodgkin’slymphoma. Ourresults encourage further studies evaluating the role of TIGIT as a target for immunotherapies in Hodgkin’slymphoma. Keywords: TIGIT, PD-1, Immune checkpoint, Hodgkin’slymphoma Introduction PD-1/PD-L1 axis may hold promise in these refractory or Hodgkin’s lymphoma (HL) is a malignant transformation relapsed Hodgkin’s lymphomas [5–7]. of B cell origin that accounts for about 20–30% of lymph- T cell immunoglobulin and ITIM domain (TIGIT), a omas in Western societies [1–3]. Although the majority of co-inhibitory transmembrane glycoprotein of the polio- Hodgkin’s lymphoma patients are curable with a virus receptor (PVR)/−nectin superfamily, is another multi-agent chemotherapy and/ or radiotherapy protocol, interesting candidate for novel checkpoint therapies [8, 9]. about 10–20% of patients develop therapy refractory dis- Using multiplex fluorescence immunohistochemistry, we ease . A characteristic feature of HL is the presence of have recently shown that TIGIT typically co-localizes with few malignant cells, including Hodgkin cells, Reed-Stern- PD-1 on CD8+ cytotoxic T cells, CD4+ T helper cells and berg cells and histiocytic cells, in a high background of in- FOXP3 regulatory T cells . Tumor associated lympho- flammatory cells. Current clinical trials provide first cytes expressing TIGIT have so far been demonstrated in evidence that immune checkpoint inhibitors targeting the acute myeloid leukemia, non-small cell lung cancer, colo- rectal carcinoma and melanoma [11–13]. Although the downstream signaling cascade of TIGIT has not been clarified, there is evidence that TIGIT negatively regulates * Correspondence: R.Simon@uke.de Wenchao Li and Niclas C. Blessin contributed equally to this work. T cell activity through downregulation of T cell receptor Department of Pathology, University Medical Center Hamburg-Eppendorf, expression [8, 14, 15]. In mouse models and ongoing clin- Martinistr. 52, 20246 Hamburg, Germany ical studies, blockade or ablation of TIGIT, alone or in Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Li et al. BMC Cancer (2018) 18:1209 Page 2 of 8 combination with blockade of programmed cell death pro- tissue microarrays and their analysis for research purposes tein (PD-1), can restore tumor suppressive effects [11, 12, as well as patient data analysis has been approved by local 16–18]. These findings indicate that TIGIT, similar to laws (HmbKHG, §12,1) and by the local ethics committee PD-1, has a crucial role in inhibiting the tumor-directed (Ethics commission Hamburg, WF-049/09). immune response and, thus, might be a suitable and relevant target for novel immune-modulating therapies. Immunohistochemistry Several drugs targeting TIGIT are currently under Freshly cut 4 μm tissue sections were used for immuno- development . histochemistry (IHC) analyses. For brightfield IHC, tissue As to yet, data on the possible role of TIGIT in sections were dewaxed and incubated in an autoclave for Hodgkin’s lymphoma are lacking. Here, we made use of 5 min at 121 °C in Tris-EDTA pH 7.8 antigen retrieval a microenvironment (ME) tissue microarray (TMA) that solution prior to blocking of endogenous peroxidase and was constructed from 2 mm tissue punches each from incubation of the primary antibody (Dianova mouse anti 40 Hodgkin’s lymphomas and studied patterns of TIGIT TIGIT, clone TG-1,1:70). Bound antibody was detected and PD-1 expression by means of conventional bright with the DAB-kit (DAKO, Santa Clara, United States) and field and multiplex fluorescence immunohistochemistry. slides were counterstained and sealed in EUKITT®. For fluorescence multiplex IHC, the Opal™ dye kit (Cat. Material and methods #OP7DS1001KT, Perkin Elmer, Waltham, Massachusetts, Tissues United States) was used. The experimental procedure was Formalin-fixed paraffin-embedded tissue samples from 40 performed according to the manufacturer’s instructions. patients with Hodgkin’s lymphoma were selected from the Slides were initially boiled in a microwave oven for 15 min archives of the institute of Pathology of the University Med- at 100 °C for antigen retrieval. Three different primary ical Center Hamburg-Eppendorf, Germany. The selection antibodies were combined with DAPI staining in each included 30 patients diagnosed with nodular sclerosis clas- experiment. One circle of antibody staining included per- sical HL (NSCHL), 7 patients with mixed cellularity oxidase blocking, application of the primary antibody, classical HL (MCCHL), one patient with lymphocyte rich detection with a secondary HRP-conjugated antibody, classical HL (LRCHL), and one patient with nodular fluorescence dye detection, and removal of the bound lymphocyte predominance HL (NLPHL). The histological antibodies by microwave treatment (15 min at 100 °C). subtype was undetermined for another patient. This cycle was repeated two times for the remaining anti- bodies. Slides were subsequently counterstained with Microenvironment (ME) TMA construction diamidino-2-phenylindole (DAPI) and mounted in anti- A pathologist reviewed all cases and selected areas con- fade solution. Details on the used antibodies, antibody re- taining Hodgkin and Reed-Sternberg cells for TMA trieval procedures and Opal™ dyes are given in Table 1. construction. A single tissue punch measuring 2 mm in diameter was taken from each donor tissue block to cap- Quantification of TIGIT and PD-1 expression ture the lymphocytic background adjacent to the malig- Digital images of multiplex immunofluorescence stain- nant cells. In addition, two punches of normal human ings were acquired using a Leica Aperio VERSA 8 auto- tonsil were added to the TMA as a reference tissue for mated epifluorescence microscope. For initial image fluorescence measurement normalization. The usage of acquisition, exposure time was manually adjusted for archived diagnostic left-over tissues for manufacturing of each fluorochrome to minimize auto fluorescence. Table 1 List of the used antibodies, antigen retrieval (AR), dilutions and Opal™ dyes Bright field Fluorescence Antibody Target AR Dilution AR Dilution Order Dye DAKO #IR503 CD3 pH 9 1:1 pH 9 1:1 1st Opal 520 DAKO #IR649 CD4 pH 9 1:1 pH 9 1:1 1st Opal 520 a b DAKO #IR623 CD8 pH 9 1:1 pH 9 1:1 1st Opal 520 BioLegend #320102 FOXP3 pH 9 1:50 pH 9 1:50 1st Opal 520 a b DAKO #IR604 CD20 pH 9 1:1 pH 9 1:10 1st Opal 520 Dianova #DIA-TG1 TIGIT pH 7.8 1:70 pH 9 1:150 2nd Opal 570 Abcam #ab52587 PD-1 pH 6 1:50 pH 6 1:50 3rd Opal 690 Order , order refers to the sequence of antibodies in multiplex fluorescence immunohistochemistry experiments antibody was used at third position when stained in combination with CD3, CD4 with Opal™ 690 dye Li et al. BMC Cancer (2018) 18:1209 Page 3 of 8 Subsequently, a threshold for positive staining was de- (500 from each tonsil), considered this expression level as fined as follows: The fluorescence intensity of each anti- 100% and used it as the reference value to estimate the body was measured in 50 to 200 cells of a cell type with staining intensity of TIGIT and PD-1 on CD3 positive known lack of expression and the fluorescence value of cells in the lymphocytic background of HL (relative the cell with highest “false positive” measurement was expression, RE). In addition, the expression level of CD3 used to define the cutoff value for positive expression. was used as an immunoreactivity control to indicate After slide scanning, image analysis was performed potential fixation or processing artefacts. using Image Scope software package (Leica Microsystems Wetzlar, Germany). Image analysis included segmentation Statistics of individual cells and subsequent measurement of the JMP Pro 12 software package (SAS Institute Inc., NC, fluorescence intensity (concentration as dye intensity per USA) analysis of variance (ANOVA) test was employed μm ). Tissue areas for analysis were manually defined and to calculate compartment specific expression differences typically included between 18,000 and 30,000 cells. Fluor- of PD-1 and TIGIT in tissue samples. escence intensity values were recorded for each fluoro- chrome in each cell. The average fluorescence intensity of Results all cells of the same compartment from all measured areas TIGIT brightfield immunohistochemistry was calculated and used for comparisons. Because staining All 40 HL included in this study were successfully ana- intensity largely depends on antibody specification and lyzed and showed detectable TIGIT staining in 9–99% staining protocols we sought to introduce a reference tis- (Median: 86%) of the lymphocytic background cells by sue for staining normalization to our experiments. We means of conventional bright field immunohistochemistry. selected two samples of tonsil tissue, which were placed Representative images are shown in Fig. 1.Bymanualin- on the same TMA along with the study samples. In our spection of the stained slide, highest staining intensities previous study , we found that cells located within the were found in a case of NLPHL. Additional experiments germinal centers of tonsil tissues had the highest TIGIT with serial dilutions of the TIGIT antibody confirmed the and PD-1 expression level of all human normal tissues. presence of T cells with extraordinary high levels of TIGIT We calculated an average from approximately 1000 lym- expression (i.e. exceeding that of normal human tonsils phocytes located at the periphery of the germinal centers germinal centers) particularly in NLPHL (Additional file 1: Fig. 1 Representative images of CD3, TIGIT and PD-1 staining in nodular lymphocyte predominance HL (NLPHL), nodular sclerosis classical HL (NSCHL), mixed cellularity classical HL (MCCHL) and lymphocyte rich classical HL (LRCHL). Insets show magnifications of Hodgkin and Reed- Sternberg cells surrounded by TIGIT and PD-1 expressing CD3 positive T cells Li et al. BMC Cancer (2018) 18:1209 Page 4 of 8 Figure S1). Also, staining intensity of the T cell rosettes example, the top 10 % of TIGIT and PD-1 positive T cells surrounding malignant (HRS and LP) cells in NLPHL and averaged 241% RE and 408% RE, respectively. in LRCHL appeared somewhat stronger as compared to scattered CD3 positive lymphocytes in the vicinity (Fig. 1). Discussion The data from this study demonstrate that TIGIT is fre- Multiplex fluorescence immunohistochemistry quently expressed in cells of the lymphocytic back- We performed multiplex fluorescence immunohisto- ground accompanying HL and that the frequency and chemistry to unravel the immune cell types expressing intensity of TIGIT expression varies markedly between TIGIT and to quantify TIGIT expression among individ- individual patients. ual patients. TIGIT was virtually undetectable on CD20 All 40 HL analyzed in our study showed detectable positive B lymphocytes but expressed on a large fraction TIGIT expression in all types of CD3 positive T cells (70%) of CD3 positive T lymphocytes. Further analysis including CD8 cytotoxic T cells, CD4 positive T helper revealed that TIGIT positive T cell subtypes included cells, and FOXP3 positive regulatory T cells. This corre- CD8 cytotoxic T cell, CD4 helper T cells and FOXP3 sponds to the situation in other normal and inflamed tis- regulatory T cells (Fig. 2). Interestingly, relative expres- sues, where we also found that TIGIT expression was sion (RE) levels of TIGIT were highly variable among largely limited to these three major types of immune individual patients and different HL subtypes. When cells. In this earlier study, we also found that TIGIT compared to the RE level found in the reference tissue expression often paralleled PD-1 expression in these (normal human tonsil germinal center periphery set to cells. It was therefore expected that a large fraction 100% RE), TIGIT RE in CD3 positive T cells ranged (more than 80%) of TIGIT positive T cells also expressed between 1 and 122% in different patients. Most patients PD-1 in our study. In normal lymph nodes and tonsils, had TIGIT expression levels equaling less than 50% of TIGIT and PD-1 co-expression was found in 50–99% of the reference tissue. Again, highest TIGIT expression T cells depending on the analyzed T cell subtype . (122%) was seen in one case of nodular lymphocyte-pre- These findings are in line with a study describing that dominant HL (NLPHL, Fig. 3). TIGIT (and PD-1) are constitutively expressed on about one third of circulating FOXP3 positive regulatory T Relationship between TIGIT and PD-1 expression cells and highly upregulated on regulatory T cells in an To estimate the fraction of CD3 positive T cells expressing inflamed microenvironment [20, 21]. This suggests that TIGIT only, PD-1 only, both, or none of the two, we the lymphocytic background of HL is affected by the focused on the largest HL subtype (n = 30 NSCHL). On same immunoregulatory mechanisms that also apply in average across all patients, it showed that the majority inflammatory and cancerous tissues. (68%) of T cells had co-expression of TIGIT and PD-1, In contrast to many other studies that reported PD-1 while isolated positivity for TIGIT and PD-1 was seen in staining in 20–60% of classical HL [22–27], we detected only 14 and 5%. The remaining 13% T cells had neither PD-1 positive lymphocytes in all analyzed cases. Some of TIGIT nor PD-1 expression (Fig. 4). Fluorescence mea- the discrepant findings may be related to different defi- surements further confirmed presence of T cells with very nitions of PD-1 positivity in earlier work, for example high levels of TIGIT and PD-1 expression in NLPHL. For studies where PD-1 positivity was assumed only when Fig. 2 Representative multiplex immunofluorescence images showing TIGIT and PD-1 staining in CD4 positive T helper cells (top panel), CD8 positive cytotoxic T cells (middle panel) and FOXP3 regulatory T cells (bottom panel) Li et al. BMC Cancer (2018) 18:1209 Page 5 of 8 Fig. 3 Variability of TIGIT (left) and PD-1 (right) expression in CD3 positive T cells in the lymphocytic background of different types of Hodgkin’s lymphoma (HL). Relative expression refers to the fluorescence measurement in normal human tonsils germinal centers set to 100%. NLPHL, nodular lymphocyte predominance HL; NSCHL, nodular sclerosis classical HL; MCCHL, mixed cellularity classical HL; LRCHL, lymphocyte rich classical HL. Bars in the box indicate expression levels of CD3 as an indicator of immunoreactivity of the analyzed tissue samples more than 20% of cells  or more than 23 cells/mm  had detectable PD-1 staining. While it is obviously impossible to explain all discrepant reports, we previ- ously found that certain levels of TIGIT and PD-1 expression are characteristic features of lymphatic infiltrations in a wide range of inflamed and cancerous tissue . The fluorescence approach enabled us to quantify the expression level of TIGIT and PD-1. We have recently shown that highest physiological TIGIT and PD-1 expres- sion was found in follicular T helper cells residing at the periphery of germinal centers in lymph nodes and tonsils . Given this consistently high expression levels and because of the easiness to identify follicular T cells, we have used these cells as a reference to compare the vari- able TIGIT and PD-1 expression of T cells located in other Fig. 4 Average fractions of CD3 positive T cells expressing TIGIT only tissue areas. Accordingly, all measured intensity levels that (green), PD-1 only (red), both (yellow) or neither one (blue) in 30 were lower than 100% do, however, not imply reduced cases of nodular lymphocyte predominance HL (NSCHL) TIGIT and PD-1 expression of the respective cells. We Li et al. BMC Cancer (2018) 18:1209 Page 6 of 8 recorded a stunning degree of TIGIT and PD-1 expression this disease [38–41]. Phase I/II studies using nivolumab level variability across the different HL specimens ana- as a combination or second line therapy in combination lyzed. The much less variable expression levels of CD3 in with or after anti-CD30 treatment in patients with re- our cancers argue against relevant fixation related varia- lapsed and refractory Hodgkin’s lymphoma reported tions in tissue immunoreactivity as a possible reason for over all response rates of 66–85% [38, 39]. Combining the observed interindividual TIGIT expression differences. immunotherapies is another option to increase response Biological reasons for the variable expression might rates. For example, combination of anti-PD-1 and include modulation of the immune environment by the anti-CTLA4 drugs has demonstrated additive efficacy in Hodgkin and Reed-Sternberg (HRS) cells or the lympho- melanomas, non-small-cell lung cancer and renal cell cytic background itself. For example, it has been suggested carcinoma [6, 42, 43]. At present, several drugs directed that the expression of PD-1 on T cells is likely driven by against TIGIT are in preclinical pipelines [17, 19]. In our constitutive upregulation of its ligands, PD-L1 and PD-L2, study, TIGIT and PD-1 expression was found in all ana- on HRS cells  and that HRS cells as well as some leu- lyzed HL and was not limited to a specific subtype. kocytes (e.g. helper and regulatory T cells or macrophages) These findings identify HL as a disease entity where it  can selectively express immunomodulatory proteins could be interesting to determine whether TIGIT inhibi- connected to PD-1 signaling such as galectin 1 and IL 10 tors alone or in combination with other immunother- [30, 31]. Hence, it is tempting to speculate that also the apies and anti-CD30 treatment might be effective. It level of TIGIT expression may be influenced by regulatory might be speculated, that the variable levels of TIGIT molecules in a similar way as known from PD-1. expression could correspond to variable responses to Notably, our series of HL included one case of nodular putative therapies targeting TIGIT. lymphocyte predominant Hodgkin’s lymphoma (NLPHL). The large tissue size TMA (ME-TMAs) enable the ana- A unique feature of NLPHL is that the lymphocytic pre- lysis for large enough tissue areas to study a tumor’s dominant (LP) cells (previously known as “popcorn” cells) microenvironment under perfectly standardized experi- arise in a follicular like microenvironment that shares mental conditions. Having all tissue samples of a study on characteristics of germinal centers in lymph nodes and one glass slide ensures not only fully identical staining tonsils, such as a high density of follicular T helper cells procedures for every tissue specimen but also identical [32, 33]. That highest TIGIT and PD-1 levels in our section thickness and slide age . This is important for current study were also found in a HL subtype with a experimental standardization as automated immunostai- characteristic follicular architecture suggests an important ners are not yet perfectly dealing with the requirements of function of these receptors in dense meshworks of leuco- multiplex fluorescence immunohistochemistry. cytes. Highest levels of TIGIT and PD-1 in tightly packed In summary, the results of our study identify HL as a lymphocytic rosettes surrounding the neoplastic cells fits tumor type with frequent but variable expression of well to the concept of compensatory downregulation of immune checkpoint receptors such as TIGIT and PD-1. excessive inflammatory reactions through immune check- Patients with HL might benefit from potential future point upregulation [34, 35]. Exceedingly high PD-1 therapies targeting TIGIT alone or in combination with expression levels in NLPHL has earlier been described other drugs. and PD-1 expression analysis was suggested as a diagnos- tic feature for this rare HL subtype . Our fluorescent Additional file measurement revealed that the TIGIT and PD-1 expres- Additional file 1: Figure S1. Serial dilution of the TIGIT antibody in sion in individual T cells could reach 2 to 4-fold higher lymph node and a NLPHL. (PDF 6352 kb) levels than those found in normal human tonsils. Another feature of HL is that the tumor cells have Acknowledgements developed mechanisms to escape the excessive immune We thank Christina Möller-Koop, Inge Brandt, Melanie Witt and Janett -cell infiltration of the host. For example, the cellular Lüttgens for excellent technical assistance. landscape of HL is characterized by a paucity of specific Funding cytotoxic T cells and natural killer (NK) cells . Much None. hope is, therefore, put on novel therapeutic strategies Availability of data and materials modulating the immune system and its response to the All relevant data and materials are included in the manuscript. For the full disease, particularly in heavily treated relapsed or refrac- detailed data, please contact the corresponding author. tory HL where effective therapies are lacking. After promising results were reported from a first clinical trial Authors’ contributions Conception and design: GS, AH, NB, RS, KF. Development of methodology:  using the PD-1 inhibitor nivolumab in chemotherapy WL, NB, RS, GS, KF. Acquisition of data (provided animals, acquired and refractory HL, a number of follow up studies have con- managed patients, provided facilities, etc.): WL, NB, BW, TM, ND, LP, AH, DH, firmed the potential of immune checkpoint therapy in ML, JI, SM, FB, RU, DD, TK, AL, CW, FJ, EB, SS, WW. Analysis and interpretation Li et al. BMC Cancer (2018) 18:1209 Page 7 of 8 of data (e.g., statistical analysis, biostatistics, computational analysis): NB, RS, 15. Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, Levin SD, Sharpe AH, WL, GS, AH. Writing, review, and/or revision of the manuscript: RS, GS, NB, Kuchroo VK. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J AH. Administrative, technical, or material support (i.e., reporting or organizing Immunol. 2011;186(3):1338–42. data, tissue processing, antibody development): MK, CH-M, GM-F, DH, ML, JI, 16. Blake SJ, Dougall WC, Miles JJ, Teng MW, Smyth MJ. Molecular pathways: SM, FB, RU, DD, TK, AL, CW, FJ, EB SS, WW. Study supervision: GS, RS, and AH. targeting CD96 and TIGIT for Cancer immunotherapy. Clin Cancer Res. 2016; All authors read and approved the final manuscript. 22(21):5183–8. 17. Dougall WC, Kurtulus S, Smyth MJ, Anderson AC. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. 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BMC Cancer – Springer Journals
Published: Dec 4, 2018
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