T-cell exhaustion in the tumor microenvironment

Y Jiang, Y Li, B Zhu, Y Jiang, Y Li, B Zhu

Abstract

T-cell exhaustion was originally identified during chronic infection in mice, and was subsequently observed in humans with cancer. The exhausted T cells in the tumor microenvironment show overexpressed inhibitory receptors, decreased effector cytokine production and cytolytic activity, leading to the failure of cancer elimination. Restoring exhausted T cells represents an inspiring strategy for cancer treatment, which has yielded promising results and become a significant breakthrough in the cancer immunotherapy. In this review, we overview the updated understanding on the exhausted T cells in cancer and their potential regulatory mechanisms and discuss current therapeutic interventions targeting exhausted T cells in clinical trials.

Figures

Figure 1
Figure 1
T-cell exhaustion and differentiation in TME. Naive T cells (CD44lowCD62Lhi) activate and differentiate into effector T cells (CD44hiCD62Llow) in secondary lymphoid organ. When effector T cells enter TME, they are polarized into exhausted T cells, with decrease in effector cytokines (IL-2/IFN-γ/TNF-α/GzmB) and increase in inhibitory receptors (PD-1/CTLA-4/TIM-3/LAG-3//BTLA/TIGIT). Subsequently exhausted T cells may turn to be defective memory T cells or be deleted physically
Figure 2
Figure 2
Potential regulatory mechanisms of T-cell exhaustion in TME. Cancer cells and stromal cells (tumor-associated DC, Treg, TAM and MDSC) are major extrinsic cells that regulate T-cell exhaustion, and IL-10 and TGF-β are both important extrinsic cytokines involved in exhausted process of T cells. Inhibitory receptors PD-1, CTLA-4, Tim-3, BTLA, LAG-3 and TIGIT on T cells are the major intrinsic regulatory factors of T-cell exhaustion. SHP-2 is the downstream of PD-1, IRF-9 and AP-1, which regulate PD-1 expression in transcriptional level

References

    1. Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol 2004; 78: 5535–5545.
    1. Kim PS, Ahmed R. Features of responding T cells in cancer and chronic infection. Curr Opin Immunol 2010; 22: 223–230.
    1. Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002; 2: 251–262.
    1. Schluns KS, Lefrancois L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol 2003; 3: 269–279.
    1. Baitsch L, Fuertes-Marraco SA, Legat A, Meyer C, Speiser DE. The three main stumbling blocks for anticancer T cells. Trends Immunol 2012; 33: 364–372.
    1. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 1998; 188: 2205–2213.
    1. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006; 439: 682–687.
    1. Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA 2010; 107: 14733–14738.
    1. Crawford A, Wherry EJ. The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses. Curr Opin Immunol 2009; 21: 179–186.
    1. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10: 29–37.
    1. Fourcade J, Sun Z, Pagliano O, Guillaume P, Luescher IF, Sander C et al. 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.
    1. Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, Levin SD et al. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 2011; 186: 1338–1342.
    1. Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12: 492–499.
    1. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 2003; 77: 4911–4927.
    1. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002; 99: 12293–12297.
    1. Murakami N, Riella LV. Co-inhibitory pathways and their importance in immune regulation. Transplantation 2014; 98: 3–14.
    1. Maj T, Wei S, Welling T, Zou W. T cells and costimulation in cancer. Cancer J 2013; 19: 473–482.
    1. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol 2015; 36: 265–276.
    1. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 2007; 27: 670–684.
    1. Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 2008; 111: 3220–3224.
    1. Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D et al. PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 2009; 182: 5240–5249.
    1. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009; 114: 1537–1544.
    1. Gehring AJ, Ho ZZ, Tan AT, Aung MO, Lee KH, Tan KC et al. Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 2009; 137: 682–690.
    1. Saito H, Kuroda H, Matsunaga T, Osaki T, Ikeguchi M. Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer. J Surg Oncol 2013; 107: 517–522.
    1. Chen J, Wu XJ, Wang GQ. Hepatoma cells up-regulate expression of programmed cell death-1 on T cells. World J Gastroenterol 2008; 14: 6853–6857.
    1. Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 2001; 19: 565–594.
    1. Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Annu Rev Immunol 2006; 24: 65–97.
    1. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 2013; 73: 3591–3603.
    1. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25: 9543–9553.
    1. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010; 207: 2187–2194.
    1. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C et al. 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.
    1. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 2012; 72: 917–927.
    1. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T 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.
    1. Derre L, Rivals JP, Jandus C, Pastor S, Rimoldi D, Romero P et al. BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. J Clin Invest 2010; 120: 157–167.
    1. Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, Irving B et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 2009; 10: 48–57.
    1. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest 2015; 125: 2046–2058.
    1. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26: 923–937.
    1. Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM, Reiner SL et al. A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity 2009; 31: 309–320.
    1. Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MA et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol 2011; 12: 663–671.
    1. Agnellini P, Wolint P, Rehr M, Cahenzli J, Karrer U, Oxenius A. Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. Proc Natl Acad Sci USA 2007; 104: 4565–4570.
    1. Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 2010; 16: 1147–1151.
    1. Terawaki S, Chikuma S, Shibayama S, Hayashi T, Yoshida T, Okazaki T et al. IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol 2011; 186: 2772–2779.
    1. Xiao G, Deng A, Liu H, Ge G, Liu X. Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1. Proc Natl Acad Sci USA 2012; 109: 15419–15424.
    1. Utzschneider DT, Legat A, Fuertes Marraco SA, Carrie L, Luescher I, Speiser DE et al. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat Immunol 2013; 14: 603–610.
    1. Wherry EJ, Barber DL, Kaech SM, Blattman JN, Ahmed R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc Natl Acad Sci USA 2004; 101: 16004–16009.
    1. Lu B, Finn OJ. T-cell death and cancer immune tolerance. Cell Death Differ 2008; 15: 70–79.
    1. Shi F, Shi M, Zeng Z, Qi RZ, Liu ZW, Zhang JY et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 2011; 128: 887–896.
    1. Xia Y, Chen R, Ye SL, Sun R, Chen J, Zhao Y. Inhibition of T-cell responses by intratumoral hepatic stellate cells contribute to migration and invasion of hepatocellular carcinoma. Clin Exp Metastasis 2011; 28: 661–674.
    1. Goding SR, Wilson KA, Xie Y, Harris KM, Baxi A, Akpinarli A et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol 2013; 190: 4899–4909.
    1. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 2005; 11: 2947–2953.
    1. Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009; 15: 971–979.
    1. Kim JR, Moon YJ, Kwon KS, Bae JS, Wagle S, Kim KM et al. Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas. PLoS One 2013; 8: e82870.
    1. Fay AP, Signoretti S, Callea M, Telomicron GH, McKay RR, Song J et al. Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study. J Immunother Cancer 2015; 3: 3.
    1. Zhang Y, Wang L, Li Y, Pan Y, Wang R, Hu H et al. Protein expression of programmed death 1 ligand 1 and ligand 2 independently predict poor prognosis in surgically resected lung adenocarcinoma. Onco Targets Ther 2014; 7: 567–573.
    1. Muenst S, Schaerli AR, Gao F, Daster S, Trella E, Droeser RA et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 2014; 146: 15–24.
    1. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 2007; 104: 3360–3365.
    1. Maine CJ, Aziz NH, Chatterjee J, Hayford C, Brewig N, Whilding L et al. Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer. Cancer Immunol Immunother 2014; 63: 215–224.
    1. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 2010; 116: 1757–1766.
    1. Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 expressions in pancreatic carcinoma. World J Surg 2010; 34: 1059–1065.
    1. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007; 13: 2151–2157.
    1. Karim R, Jordanova ES, Piersma SJ, Kenter GG, Chen L, Boer JM et al. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res 2009; 15: 6341–6347.
    1. Shi SJ, Wang LJ, Wang GD, Guo ZY, Wei M, Meng YL et al. B7-H1 expression is associated with poor prognosis in colorectal carcinoma and regulates the proliferation and invasion of HCT116 colorectal cancer cells. PLoS One 2013; 8: e76012.
    1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–2454.
    1. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med 2015; 21: 24–33.
    1. Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC. Regulatory T cells in cancer. Adv Cancer Res 2010; 107: 57–117.
    1. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer 2010; 127: 759–767.
    1. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007; 110: 1225–1232.
    1. Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5'-adenosine monophosphate to adenosine. J Immunol 2006; 177: 6780–6786.
    1. Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998; 188: 287–296.
    1. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005; 6: 1142–1151.
    1. Annacker O, Asseman C, Read S, Powrie F. Interleukin-10 in the regulation of T cell-induced colitis. J Autoimmun 2003; 20: 277–279.
    1. Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 2005; 8: 369–380.
    1. Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 2007; 117: 2570–2582.
    1. Hurwitz AA, Watkins SK. Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells. Cancer Immunol Immunother 2012; 61: 289–293.
    1. Allavena P, Mantovani A. Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 2012; 167: 195–205.
    1. Mantovani A, Ming WJ, Balotta C, Abdeljalil B, Bottazzi B. Origin and regulation of tumor-associated macrophages: the role of tumor-derived chemotactic factor. Biochim Biophys Acta 1986; 865: 59–67.
    1. Murdoch C, Tazzyman S, Webster S, Lewis CE. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J Immunol 2007; 178: 7405–7411.
    1. Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006; 66: 605–612.
    1. Bottazzi B, Walter S, Govoni D, Colotta F, Mantovani A. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma. J Immunol 1992; 148: 1280–1285.
    1. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23: 549–555.
    1. Dannenmann SR, Thielicke J, Stockli M, Matter C, von Boehmer L, Cecconi V et al. Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma. Oncoimmunology 2013; 2: e23562.
    1. Bronte V. Myeloid-derived suppressor cells in inflammation: uncovering cell subsets with enhanced immunosuppressive functions. Eur J Immunol 2009; 39: 2670–2672.
    1. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009; 182: 4499–4506.
    1. Liu Y, Zeng B, Zhang Z, Zhang Y, Yang R. B7-H1 on myeloid-derived suppressor cells in immune suppression by a mouse model of ovarian cancer. Clin Immunol 2008; 129: 471–481.
    1. Yang R, Cai Z, Zhang Y, Yutzy WH 4th, Roby KF, Roden RB. CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells. Cancer Res 2006; 66: 6807–6815.
    1. Kim YJ, Park SJ, Broxmeyer HE. Phagocytosis, a potential mechanism for myeloid-derived suppressor cell regulation of CD8+ T cell function mediated through programmed cell death-1 and programmed cell death-1 ligand interaction. J Immunol 2011; 187: 2291–2301.
    1. Massague J. TGFbeta in cancer. Cell 2008; 134: 215–230.
    1. Katz LH, Li Y, Chen JS, Munoz NM, Majumdar A, Chen J et al. Targeting TGF-beta signaling in cancer. Expert Opin Ther Targets 2013; 17: 743–760.
    1. Trapani JA. The dual adverse effects of TGF-beta secretion on tumor progression. Cancer Cell 2005; 8: 349–350.
    1. Lin R, Chen L, Chen G, Hu C, Jiang S, Sevilla J et al. Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression. J Clin Invest 2014; 124: 5352–5367.
    1. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198: 1875–1886.
    1. Strauss L, Bergmann C, Gooding W, Johnson JT, Whiteside TL. The frequency and suppressor function of CD4+CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 2007; 13: 6301–6311.
    1. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014; 2014: 149185.
    1. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev 2001; 182: 68–79.
    1. Momtaz P, Postow MA. Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. Pharmgenomics Pers Med 2014; 7: 357–365.
    1. Graziani G, Tentori L, Navarra P. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res 2012; 65: 9–22.
    1. Camacho LH, Antonia S, Sosman J, Kirkwood JM, Gajewski TF, Redman B et al. Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol 2009; 27: 1075–1081.
    1. Kyi C, Postow MA. Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett 2014; 588: 368–376.
    1. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 2008; 14: 3044–3051.
    1. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369: 134–144.
    1. Ramalingam SS, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ et al. Phase II study of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer: metastatic non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2014; 90: 1266–1267.
    1. Tykodi SS. PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence. Onco Targets Ther 2014; 7: 1349–1359.
    1. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014; 515: 558–562.
    1. Lu J, Lee-Gabel L, Nadeau MC, Ferencz TM, Soefje SA. Clinical evaluation of compounds targeting PD-1/PD-L1 pathway for cancer immunotherapy. J Oncol Pharm Pract 2014; e-pub ahead of print 9 Jun 2014.
    1. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372: 2006–2017.

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