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    Topic review

    Inhibitory Checkpoint Receptors

    Subjects: Oncology
    View times: 10
    Submitted by: Joshua Tobin

    Definition

    Inhibitory checkpoint receptors play a critical role in immune homeostasis. In health, the expression of checkpoint receptors is upregulated following the activation of antigen specific T-cells to temper the pro-inflammatory response. However, upon prolonged activation with a persisting antigen, such as chronic viral infections or in cancer, checkpoint expression is maintained, and effector T-cells enter a state of 'exhaustion'. Exhausted T-cells demonstrate a progressively reduced proliferative capacity and the loss of effector T-cell functions including the production of inflammatory cytokines and degranulation. Accordingly, there has been a rapid expansion in therapeutic targeting of these checkpoint receptors to reinvigorate the effector functions of exhausted T-cells.

    1. Introduction

    Therapeutic immune checkpoint blockade (ICB) of Programmed Death-1 (PD-1) receptor has shown remarkable efficacy in restoring effector T-cell function in malignancy and consequent clinical trials have shown unprecedented therapeutic gains in many solid tumors including melanoma, non-small cell lung cancers (NSCLC), and renal cell carcinoma [1][2][3]. Unfortunately, trials of PD-1 blockade in lymphoma have been less successful and clinical responses have been limited to a proportion of patients with Hodgkin lymphoma and rare Non-Hodgkin Lymphoma (NHL) subtypes. The reasons for the sub-optimal efficacy of these agents in lymphoma remain unclear and are an area of active research.
    Nevertheless, the promising anti-tumor activity of these agents in a narrow range of lymphoma subsets has prompted continued interest in the development of newer checkpoint inhibitors and the employment of rational combinations of ICB agents to overcome T-cell exhaustion in lymphoproliferative diseases (LPDs).

    2. Checkpoint Molecules in Non-Hodgkin Lymphoma

    2.1. Immune Checkpoint Molecules in Primary Mediastinal B-Cell Lymphoma

    PMBCL is distinct from other B-NHL subtypes demonstrating clinical, morphological, and molecular features shared with cHL [4]. The genetic hallmarks of PMBCL are copy number alterations or translocations of the PDCDLG1 and PDCDLG2 genes (encoding PD-L1 and PD-L2, respectively) at locus 9p24.1 which are present in 60–70% of cases [5][6]. These genomic alterations occur at significantly higher frequency in PMBCL than other B-NHL subtypes. Accordingly, this correlates with increased PD-1 ligand expression on tumor cells [7][8][9]. Translocations of the 9p locus are highly specific for PMBCL often involving PDCDLG2 (gene encoding PD-L2) and lead to expression of PD-L2 at higher levels than PD-L1, a phenomenon not seen in other B-LPDs, including cHL [10][6][8][11]. MHC class II transactivator (CIITA), is a recurrent gene fusion partner for 9p.24 translocations in PMBCL which further reduced tumor immunogenicity through decreased antigen presentation and these translocations are associated with poorer outcomes [9].
    PMBCL has recently been described to have high expression of LAG-3 within the TME at similar levels to that found in cHL. However, in this study, the authors found the vast majority of T-cells in PMBCL with LAG-3 expression were on CD8+ TILs [12] in contrast to cHL where CD4+ TILs appeared to be the predominant LAG-3 expressing T-cell [13]. Data regarding the functional status of these TILs remain sparse and further description of the co-expression of other inhibitory molecules in this NHL subtype are needed.

    2.2. Immune Checkpoint Molecules in Primary Central Nervous System and Testicular Lymphoma

    Primary CNS (PCNSL) and primary testicular lymphoma (PTL) present in areas of ‘immune privilege’. Like PMBCL, more than half of PCSNL/PTL cases have genomic alterations of 9p24.1 that result in constitutive PD-1 ligand expression on tumoral cells [14]. Additional molecular drivers of the pathogenesis of PCNSL/PTL include gain-of-function MYD88 mutations (65% of cases) and loss of MHC I and II molecules (50% of PCNSL and 80% of PTL), both of which are independent of PD-1/PD-1 ligand expression [14][15].
    Given the TME and PD-1 axis have a significant role in dictating treatment outcome in PCNSL/PTL they are promising prognostic biomarker candidates. As described above, PD-L1 is over-expressed in the ‘immune privileged’ TME by several distinct mechanisms. While the total PD-L1 and tumor cells-restricted PD-L1 expression appears to have no association with clinical outcome, a favorable outcome is observed in patients with high PD-L1 expression on TAMs in both PTL and PCSNL treated with conventional therapy [16][17]. In PTL, high PD-1 expression on TILs (CD4+ and CD8+) correlates strongly with intra-tumoral PD-L1+ TAMs and is also associated with improved outcomes [17][18]. By contrast, high PD-1+ TILs in PCSNL conveys a poor prognosis, potentially reflecting high levels of T-cell exhaustion, which is particularly enriched in the rare EBVPOS subset occurring in immunocompromised patients [19][20][21][22]. Gene expression and multiplex IHC studies of PCNSL have found that co-expression of other immune checkpoint molecules (i.e., LAG-3 and TIM-3) in the TME is more strongly associated with poor outcome than PD-1 alone [18][23]. This implies that multiple markers to define states of T-cell exhaustion may be more valuable as a prognostic biomarker than PD-1 alone.
    As seen in some cases of cHL, EBV is involved in lymphomagenesis through activation of the JAK/STAT pathway and transcription factor AP-1 [24]. EBVPOS PCNSL represents a rare but distinct subset of patients typified by unique immunobiology and poorer clinical outcomes [25]. Unlike the EBVNEG counterparts, EBVPOS PCNSL seldom demonstrate increased rates of genomic alterations of 9p24.1 that could increase constitutional expression of PD-1 ligands [26]. Despite this, PD-L1 gene expression is several fold higher in EBVPOS cases which are also enriched for expression of LAG-3 and CD163 [17][27][28]. These findings are consistent with other EBV-infected LPDs including EBVPOS cHL [27][29], post-transplant lymphoproliferative disease, and plasmablastic lymphoma [30][28]. Further IHC studies have demonstrated that the majority of PD-L1/PD-L2 expression in EBVPOS PCSNL appears to be on microenvironmental cells, most notably TAMs, which co-expressed high PD-L1 and PD-L2 [15][16][17][25][31]. This is associated with significant T-cell exhaustion of intra-tumoral T-cells that co-express PD-1 along with other checkpoint molecules, LAG-3 and TIM-3 [25]. As such, EBVPOS lymphoma represent an attractive entity for trials of dual-checkpoint blockade to reinvigorate the intra-tumoral immune response.
    Together, these findings indicate that ‘immune privilege’ is conferred through a variety of mechanisms in PCSNL and PTL. EBVNEG tumors are dependent on genetically mediated immune evasion including 9p24.1 gains or translocations and loss of HLA-I/II loci whereas immune evasion in EBVPOS PCSNL is orchestrated by up-regulation of PD-L1+ M2 monocyte/macrophages along with LAG-3 upregulation and subsequent T-cell exhaustion.

    3. Future Directions

    Both PD-1 and LAG-3 represent emerging mechanisms of immune escape in LPD and are promising targets for therapeutic intervention. Pre-clinical studies suggest the synergistic role of dual blockade of these pathways may be more efficacious than either strategy alone due to improved re-activation of exhausted effector TILs as evidenced in DLBCL or by targeting separate populations in the TME as evidenced in cHL. Additionally, combinations of single or dual ICB therapy with sensitizing agents that promote immunogenic cell death (i.e., radiotherapy, immune vaccines, and oncolytic viruses) are hypothesized to improve tumor immunogenicity may broaden the cohort of patients that are responsive to immunotherapy as suggested by recent developments in FL.
    As well as opportunities to enhance immunogenicity, manipulation of the PD-1 and LAG3 axis also show promise as a strategy to improve responses to adoptive T-cell therapies such as chimeric antigen receptor T-cells (CAR-T). Studies using CRISPR-Cas9 mediated gene editing demonstrate that the knockout of PD-1 and LAG3 in CAR-T cells overcome the immunosuppressive nature of the tumor environment, a key factor limiting CAR-T efficacy [32][33][34][35]. As such, the outcomes of current clinical studies of dual checkpoint blockade and associated translational studies in lymphoproliferative disease are eagerly awaited.

    The entry is from 10.3390/cells10051152

    References

    1. Fourcade, J.; Sun, Z.; Benallaoua, M.; Guillaume, P.; Luescher, I.F.; Sander, C.; Kirkwood, J.M.; Kuchroo, V.; Zarour, H.M. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 2010, 207, 2175–2186.
    2. Fourcade, J.; Sun, Z.; Pagliano, O.; Guillaume, P.; Luescher, I.F.; Sander, C.; Kirkwood, J.M.; Olive, D.; Kuchroo, V.; Zarour, H.M. CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res. 2012, 72, 887–896.
    3. Matsuzaki, J.; Gnjatic, S.; Mhawech-Fauceglia, P.; Beck, A.; Miller, A.; Tsuji, T.; Eppolito, C.; Qian, F.; Lele, S.; Shrikant, P.; et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl. Acad. Sci. USA 2010, 107, 7875–7880.
    4. Broccoli, A.; Zinzani, P.L. The unique biology and treatment of primary mediastinal B-cell lymphoma. Best Pract. Res. Clin. Haematol. 2018, 31, 241–250.
    5. Green, M.R.; Monti, S.; Rodig, S.J.; Juszczynski, P.; Currie, T.; O’Donnell, E.; Chapuy, B.; Takeyama, K.; Neuberg, D.; Golub, T.R.; et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010, 116, 3268–3277.
    6. Twa, D.D.; Chan, F.C.; Ben-Neriah, S.; Woolcock, B.W.; Mottok, A.; Tan, K.L.; Slack, G.W.; Gunawardana, J.; Lim, R.S.; McPherson, A.W.; et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 2014, 123, 2062–2065.
    7. Carey, C.D.; Gusenleitner, D.; Lipschitz, M.; Roemer, M.G.M.; Stack, E.C.; Gjini, E.; Hu, X.; Redd, R.; Freeman, G.J.; Neuberg, D.; et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 2017, 130, 2420–2430.
    8. Zhou, H.; Xu-Monette, Z.Y.; Xiao, L.; Strati, P.; Hagemeister, F.B.; He, Y.; Chen, H.; Li, Y.; Manyam, G.C.; Li, Y.; et al. Prognostic factors, therapeutic approaches, and distinct immunobiologic features in patients with primary mediastinal large B-cell lymphoma on long-term follow-up. Blood Cancer J. 2020, 10, 49.
    9. Steidl, C.; Shah, S.P.; Woolcock, B.W.; Rui, L.; Kawahara, M.; Farinha, P.; Johnson, N.A.; Zhao, Y.; Telenius, A.; Neriah, S.B.; et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 2011, 471, 377–381.
    10. Panjwani, P.K.; Charu, V.; DeLisser, M.; Molina-Kirsch, H.; Natkunam, Y.; Zhao, S. Programmed death-1 ligands PD-L1 and PD-L2 show distinctive and restricted patterns of expression in lymphoma subtypes. Hum. Pathol. 2018, 71, 91–99.
    11. Shi, M.; Roemer, M.G.; Chapuy, B.; Liao, X.; Sun, H.; Pinkus, G.S.; Shipp, M.A.; Freeman, G.J.; Rodig, S.J. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am. J. Surg. Pathol. 2014, 38, 1715–1723.
    12. Takata, K.; Aoki, T.; Chong, L.C.; Milne, K.; Miyata-Takata, T.; Singh, K.; Goodyear, T.; Farinha, P.; Slack, G.W.; Sehn, L.H. Identification of LAG3+ T Cell Populations in the Tumor Microenvironment of Classical Hodgkin Lymphoma and B-Cell Non-Hodgkin Lymphoma. Blood 2020, 136.
    13. Nagasaki, J.; Togashi, Y.; Sugawara, T.; Itami, M.; Yamauchi, N.; Yuda, J.; Sugano, M.; Ohara, Y.; Minami, Y.; Nakamae, H. The critical role of CD4+ T cells in PD-1 blockade against MHC-II–expressing tumors such as classic Hodgkin lymphoma. Blood Adv. 2020, 4, 4069–4082.
    14. Chapuy, B.; Roemer, M.G.; Stewart, C.; Tan, Y.; Abo, R.P.; Zhang, L.; Dunford, A.J.; Meredith, D.M.; Thorner, A.R.; Jordanova, E.S.; et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 2016, 127, 869–881.
    15. Sethi, T.K.; Kovach, A.E.; Grover, N.S.; Huang, L.C.; Lee, L.A.; Rubinstein, S.M.; Wang, Y.; Morgan, D.S.; Greer, J.P.; Park, S.I.; et al. Clinicopathologic correlates of MYD88 L265P mutation and programmed cell death (PD-1) pathway in primary central nervous system lymphoma. Leuk. Lymphoma 2019, 60, 2880–2889.
    16. Furuse, M.; Kuwabara, H.; Ikeda, N.; Hattori, Y.; Ichikawa, T.; Kagawa, N.; Kikuta, K.; Tamai, S.; Nakada, M.; Wakabayashi, T.; et al. PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma. Bmc Cancer 2020, 20, 277.
    17. Pollari, M.; Brück, O.; Pellinen, T.; Vähämurto, P.; Karjalainen-Lindsberg, M.L.; Mannisto, S.; Kallioniemi, O.; Kellokumpu-Lehtinen, P.L.; Mustjoki, S.; Leivonen, S.K.; et al. PD-L1(+) tumor-associated macrophages and PD-1(+) tumor-infiltrating lymphocytes predict survival in primary testicular lymphoma. Haematologica 2018, 103, 1908–1914.
    18. Pollari, M.; Pellinen, T.; Karjalainen-Lindsberg, M.L.; Kellokumpu-Lehtinen, P.L.; Leivonen, S.K.; Leppä, S. Adverse prognostic impact of regulatory T-cells in testicular diffuse large B-cell lymphoma. Eur. J. Haematol. 2020.
    19. Cho, H.; Kim, S.H.; Kim, S.J.; Chang, J.H.; Yang, W.I.; Suh, C.O.; Kim, Y.R.; Jang, J.E.; Cheong, J.W.; Min, Y.H.; et al. Programmed cell death 1 expression is associated with inferior survival in patients with primary central nervous system lymphoma. Oncotarget 2017, 8, 87317–87328.
    20. Cho, I.; Lee, H.; Yoon, S.E.; Ryu, K.J.; Ko, Y.H.; Kim, W.S.; Kim, S.J. Serum levels of soluble programmed death-ligand 1 (sPD-L1) in patients with primary central nervous system diffuse large B-cell lymphoma. BMC Cancer 2020, 20, 120.
    21. Four, M.; Cacheux, V.; Tempier, A.; Platero, D.; Fabbro, M.; Marin, G.; Leventoux, N.; Rigau, V.; Costes-Martineau, V.; Szablewski, V. PD1 and PDL1 expression in primary central nervous system diffuse large B-cell lymphoma are frequent and expression of PD1 predicts poor survival. Hematol. Oncol. 2017, 35, 487–496.
    22. Hayano, A.; Komohara, Y.; Takashima, Y.; Takeya, H.; Homma, J.; Fukai, J.; Iwadate, Y.; Kajiwara, K.; Ishizawa, S.; Hondoh, H.; et al. Programmed Cell Death Ligand 1 Expression in Primary Central Nervous System Lymphomas: A Clinicopathological Study. Anticancer Res. 2017, 37, 5655–5666.
    23. Takashima, Y.; Kawaguchi, A.; Sato, R.; Yoshida, K.; Hayano, A.; Homma, J.; Fukai, J.; Iwadate, Y.; Kajiwara, K.; Ishizawa, S.; et al. Differential expression of individual transcript variants of PD-1 and PD-L2 genes on Th-1/Th-2 status is guaranteed for prognosis prediction in PCNSL. Sci. Rep. 2019, 9, 10004.
    24. Ok, C.Y.; Li, L.; Xu-Monette, Z.Y.; Visco, C.; Tzankov, A.; Manyam, G.C.; Montes-Moreno, S.; Dybkaer, K.; Chiu, A.; Orazi, A.; et al. Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2014, 20, 2338–2349.
    25. Marcelis, L.; Antoranz, A.; Delsupehe, A.M.; Biesemans, P.; Ferreiro, J.F.; Debackere, K.; Vandenberghe, P.; Verhoef, G.; Gheysens, O.; Cattoretti, G.; et al. In-depth characterization of the tumor microenvironment in central nervous system lymphoma reveals implications for immune-checkpoint therapy. Cancer Immunol. Immunother. 2020, 69, 1751–1766.
    26. Gandhi, M.K.; Keane, C.; Tobin, J.W.D.; Talaulikar, D.; Jain, S.; Vari, F.; Kruze, L.; Murigneux, V.; Fink, L.; Gunawardana, J.; et al. The Impact of EBV upon the Tumor Microenvironment and Mutational Profile of Primary CNS Lymphoma in PTLD. Blood 2017, 130, 2731.
    27. Jones, K.; Vari, F.; Keane, C.; Crooks, P.; Nourse, J.P.; Seymour, L.A.; Gottlieb, D.; Ritchie, D.; Gill, D.; Gandhi, M.K. Serum CD163 and TARC as disease response biomarkers in classical Hodgkin lymphoma. Clin. Cancer Res. 2013, 19, 731–742.
    28. Chen, B.J.; Chapuy, B.; Ouyang, J.; Sun, H.H.; Roemer, M.G.; Xu, M.L.; Yu, H.; Fletcher, C.D.; Freeman, G.J.; Shipp, M.A.; et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin. Cancer Res. 2013, 19, 3462–3473.
    29. Gandhi, M.K.; Lambley, E.; Duraiswamy, J.; Dua, U.; Smith, C.; Elliott, S.; Gill, D.; Marlton, P.; Seymour, J.; Khanna, R. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood 2006, 108, 2280–2289.
    30. Green, M.R.; Rodig, S.; Juszczynski, P.; Ouyang, J.; Sinha, P.; O’Donnell, E.; Neuberg, D.; Shipp, M.A. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: Implications for targeted therapy. Clin. Cancer Res. 2012, 18, 1611–1618.
    31. Miyasato, Y.; Takashima, Y.; Takeya, H.; Yano, H.; Hayano, A.; Nakagawa, T.; Makino, K.; Takeya, M.; Yamanaka, R.; Komohara, Y. The expression of PD-1 ligands and IDO1 by macrophage/microglia in primary central nervous system lymphoma. J. Clin. Exp. Hematop. 2018, 58, 95–101.
    32. Zhang, Y.; Zhang, X.; Cheng, C.; Mu, W.; Liu, X.; Li, N.; Wei, X.; Liu, X.; Xia, C.; Wang, H. CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells. Front. Med. 2017, 11, 554–562.
    33. Rupp, L.J.; Schumann, K.; Roybal, K.T.; Gate, R.E.; Ye, C.J.; Lim, W.A.; Marson, A. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 2017, 7, 737.
    34. Hu, B.; Zou, Y.; Zhang, L.; Tang, J.; Niedermann, G.; Firat, E.; Huang, X.; Zhu, X. Nucleofection with Plasmid DNA for CRISPR/Cas9-Mediated Inactivation of Programmed Cell Death Protein 1 in CD133-Specific CAR T Cells. Hum. Gene Ther. 2019, 30, 446–458.
    35. Guo, X.; Jiang, H.; Shi, B.; Zhou, M.; Zhang, H.; Shi, Z.; Du, G.; Luo, H.; Wu, X.; Wang, Y.; et al. Disruption of PD-1 Enhanced the Anti-tumor Activity of Chimeric Antigen Receptor T Cells Against Hepatocellular Carcinoma. Front. Pharmacol. 2018, 9, 1118.
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