Sự cạn kiệt tế bào T trong môi trường mô khối u

Cell Death and Disease - Tập 6 Số 6 - Trang e1792-e1792
Yuyong Jiang1, Yongsheng Li1, Bo Zhu1
1Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China

Tóm tắt

Tóm tắt

Sự cạn kiệt tế bào T đã được xác định lần đầu tiên trong các trường hợp nhiễm trùng mạn tính ở chuột, và sau đó đã được quan sát thấy ở con người mắc ung thư. Các tế bào T cạn kiệt trong môi trường mô khối u thể hiện sự biểu hiện quá mức của các thụ thể ức chế, giảm sản xuất cytokine hiệu ứng và hoạt động ly giải tế bào, dẫn đến sự thất bại trong việc loại bỏ ung thư. Việc phục hồi các tế bào T cạn kiệt đại diện cho một chiến lược đầy cảm hứng trong điều trị ung thư, đã đạt được những kết quả hứa hẹn và trở thành một bước đột phá quan trọng trong liệu pháp miễn dịch ung thư. Trong bài đánh giá này, chúng tôi tổng quan hiểu biết cập nhật về các tế bào T cạn kiệt trong ung thư và các cơ chế điều hòa tiềm năng của chúng, cũng như thảo luận về các can thiệp điều trị hiện tại nhắm vào các tế bào T cạn kiệt trong các thử nghiệm lâm sàng.

Từ khóa

#cạn kiệt tế bào T #ung thư #môi trường mô khối u #liệu pháp miễn dịch #cytokine #thụ thể ức chế

Tài liệu tham khảo

Wherry EJ, Ahmed R . Memory CD8 T-cell differentiation during viral infection. J Virol 2004; 78: 5535–5545.

Kim PS, Ahmed R . Features of responding T cells in cancer and chronic infection. Curr Opin Immunol 2010; 22: 223–230.

Kaech SM, Wherry EJ, Ahmed R . Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002; 2: 251–262.

Schluns KS, Lefrancois L . Cytokine control of memory T-cell development and survival. Nat Rev Immunol 2003; 3: 269–279.

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.

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.

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.

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.

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.

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.

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.

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.

Wherry EJ . T cell exhaustion. Nat Immunol 2011; 12: 492–499.

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.

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.

Murakami N, Riella LV . Co-inhibitory pathways and their importance in immune regulation. Transplantation 2014; 98: 3–14.

Maj T, Wei S, Welling T, Zou W . T cells and costimulation in cancer. Cancer J 2013; 19: 473–482.

Pauken KE, Wherry EJ . Overcoming T cell exhaustion in infection and cancer. Trends Immunol 2015; 36: 265–276.

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.

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.

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.

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.

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.

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.

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.

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.

Teft WA, Kirchhof MG, Madrenas J . A molecular perspective of CTLA-4 function. Annu Rev Immunol 2006; 24: 65–97.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Lu B, Finn OJ . T-cell death and cancer immune tolerance. Cell Death Differ 2008; 15: 70–79.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Johansson CC . Regulatory T cells in cancer. Adv Cancer Res 2010; 107: 57–117.

Nishikawa H, Sakaguchi S . Regulatory T cells in tumor immunity. Int J Cancer 2010; 127: 759–767.

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.

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.

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.

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.

Annacker O, Asseman C, Read S, Powrie F . Interleukin-10 in the regulation of T cell-induced colitis. J Autoimmun 2003; 20: 277–279.

Thomas DA, Massague J . TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 2005; 8: 369–380.

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.

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.

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.

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.

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.

Lewis CE, Pollard JW . Distinct role of macrophages in different tumor microenvironments. Cancer Res 2006; 66: 605–612.

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.

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.

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.

Bronte V . Myeloid-derived suppressor cells in inflammation: uncovering cell subsets with enhanced immunosuppressive functions. Eur J Immunol 2009; 39: 2670–2672.

Ostrand-Rosenberg S, Sinha P . Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009; 182: 4499–4506.

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.

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.

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.

Massague J . TGFbeta in cancer. Cell 2008; 134: 215–230.

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.

Trapani JA . The dual adverse effects of TGF-beta secretion on tumor progression. Cancer Cell 2005; 8: 349–350.

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.

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.

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.

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.

Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK . Type 1 T regulatory cells. Immunol Rev 2001; 182: 68–79.

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.

Graziani G, Tentori L, Navarra P . Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res 2012; 65: 9–22.

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.

Kyi C, Postow MA . Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett 2014; 588: 368–376.

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.

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.

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.

Tykodi SS . PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence. Onco Targets Ther 2014; 7: 1349–1359.

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.

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.

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.