PD-1 and its ligands are important immune checkpoints in cancer

Oncotarget

Volumn 8, Issue 2, 2017, Pages 2171-2186

  Dong, Yinan ^a   Sun, Qian ^a   Zhang, Xinwei ^a  

^a TIANJIN MEDICAL UNIVERSITY   (China)

Author keywords

Immune checkpoint blockade; PD 1; PD L1; PD L2; T cell anergy

Indexed keywords

ADHESION AND DEGRANULATION PROMOTING ADAPTOR PROTEIN; AMP 224; ANTINEOPLASTIC AGENT; ATEZOLIZUMAB; B LYMPHOCYTE INDUCED MATURATION PROTEIN 1; BMS 936559; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 ANTIBODY; DURVALUMAB; GAMMA INTERFERON; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INTERLEUKIN 10; INTERLEUKIN 4; INTERLEUKIN 6; INTERLEUKIN 6 RECEPTOR; MEMBRANE PROTEIN; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; NIVOLUMAB; PEMBROLIZUMAB; PIDILIZUMAB; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 RECEPTOR; SRC KINASE ASSOCIATED PROTEIN 55; STAT3 PROTEIN; STAT4 PROTEIN; TRANSCRIPTION FACTOR CTCF; TRANSCRIPTION FACTOR RELA; UNCLASSIFIED DRUG; CD274 PROTEIN, HUMAN; PDCD1 PROTEIN, HUMAN;

ADVANCED CANCER; AMINO TERMINAL SEQUENCE; ANTIBODY RESPONSE; ANTINEOPLASTIC ACTIVITY; ARTICLE; BINDING AFFINITY; BINDING SITE; CANCER SURVIVAL; CARBOXY TERMINAL SEQUENCE; CASTRATE RESISTANT PROSTATE CANCER; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CLINICAL TRIAL (TOPIC); COLORECTAL CARCINOMA; CYTOKINE RELEASE; DIFFUSE LARGE B CELL LYMPHOMA; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG TOLERABILITY; EFFECTOR CELL; GENE EXPRESSION REGULATION; HUMAN; IMMUNE CHECKPOINT; IMMUNE EVASION; IMMUNOLOGICAL PARAMETERS; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; MALIGNANT NEOPLASM; MELANOMA; MOLECULAR DYNAMICS; NON SMALL CELL LUNG CANCER; NONHUMAN; OVERALL SURVIVAL; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; SURVIVAL RATE; SURVIVAL TIME; T LYMPHOCYTE; TUMOR ASSOCIATED LEUKOCYTE; UPREGULATION; ANIMAL; CELL CYCLE CHECKPOINT; GENETICS; IMMUNOLOGY; LYMPHOCYTE; LYMPHOCYTE ACTIVATION; METABOLISM; NEOPLASM; PHYSIOLOGY;

ANIMALS; B7-H1 ANTIGEN; CELL CYCLE CHECKPOINTS; HUMANS; LYMPHOCYTE ACTIVATION; LYMPHOCYTES; LYMPHOCYTES, TUMOR-INFILTRATING; NEOPLASMS; PROGRAMMED CELL DEATH 1 RECEPTOR;

EID: 85009754361     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.13895     Document Type: Article

References (140)

1. Shindo Y, Yoshimura K, Kuramasu A, Watanabe Y, Ito H, Kondo T, Oga A, Ito H, Yoshino S, Hazama S, Tamada K, Yagita H, Oka M. Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. Anticancer Res. 2015; 35:129-136
2. Ritprajak P1, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PDL1 in epithelial cells and squamous cell carcinoma. Oral Oncol. 2015; 51: 221-228. doi: 10.1016/j. oraloncology.2014.11.014
3. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010; 236: 219-242. doi: 10.1111/j.1600-065X.2010.00923.x
4. Lázár-Molnár E, Gácser A, Freeman GJ, Almo SC, Nathenson SG, Nosanchuk JD. The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci U S A. 2008; 105: 2658-2663. doi: 10.1073/pnas.0711918105
5. Ellestad KK, Thangavelu G, Ewen CL, Boon L, Anderson CC. PD-1 is not required for natural or peripherally induced regulatory T cells: Severe autoimmunity despite normal production of regulatory T cells. Eur J Immunol. 2014; 44: 3560-3572. doi: 10.1002/eji.201444688
6. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motifcarrying immunoreceptor. Immunity. 1999; 11: 141-151
7. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001; 291: 319-322
8. Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, Vanderford TH, Chennareddi L, Silvestri G, Freeman GJ, Ahmed R, Amara RR. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009; 458: 206-210. doi: 10.1038/nature07662
9. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006; 439: 682-687
10. Ji M, Liu Y, Li Q, Li XD, Zhao WQ, Zhang H, Zhang X, Jiang JT, Wu CP. PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation. J Transl Med. 2015; 13: 5. doi: 10.1186/s12967-014-0373-0
11. Freeman-Keller M, Weber JS. Anti-programmed death receptor 1 immunotherapy in melanoma: rationale, evidence and clinical potential. Ther Adv Med Oncol. 2015; 7: 12-21 doi: 10.1177/1758834014551747
12. Huang RY, Eppolito C, Lele S, Shrikant P, Matsuzaki J, Odunsi K. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget. 2015; 6: 27359-27377. doi: 10.18632/oncotarget.4751
13. Wang SD, Li HY, Li BH, Xie T, Zhu T, Sun LL, Ren HY, Ye ZM. The role of CTLA-4 and PD-1 in anti-tumor immune response and their potential efficacy against osteosarcoma. Int Immunopharmacol. 2016; 38: 81-89. doi: 10.1016/j.intimp.2016.05.016
14. Okamura T, Fujio K, Sumitomo S, Yamamoto K. Roles of LAG3 and EGR2 in regulatory T cells. Ann Rheum Dis. 2012; 71: i96-100. doi: 10.1136/annrheumdis-2011-200588
15. Bu M, Shen Y, Seeger WL, An S, Qi R, Sanderson JA, Cai Y. Ovarian carcinoma-infiltrating regulatory T cells were more potent suppressors of CD8(+) T cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression. Tumour Biol. 2016; 37: 3949-3956. doi: 10.1007/s13277-015-4237-x
16. Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol. 2014; 153: 145-152. doi: 10.1016/j.clim.2014.04.010
17. Henick BS, Herbst RS, Goldberg SB. The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer. Expert Opin Ther Targets. 2014; 12: 1407-1420. doi: 10.1517/14728222.2014.955794
18. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013; 369: 134-144. doi: 10.1056/NEJMoa1305133
19. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366: 2443-2454. doi: 10.1056/NEJMoa1200690
20. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014; 32: 1020-1030. doi: 10.1200/JCO.2013.53.0105
21. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013; 369: 122-133. doi: 10.1056/NEJMoa1302369
22. Rajan A, Gulley JL. Gulley, Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients with advanced non-small cell lung cancer. Transl Lung Cancer Res. 2014; 3: 403-405 doi: 10.3978/j.issn.2218-6751
23. Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccin Immunother. 2016
24. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992; 11: 3887-3895
25. Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T. Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics. 1994; 23: 704-706
26. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009; 229: 114-125. doi: 10.1111/j.1600-065X.2009.00767.x
27. McPherson RC, Konkel JE, Prendergast CT, Thomson JP, Ottaviano R, Leech MD, Kay O, Zandee SE, Sweenie CH, Wraith DC, Meehan RR, Drake AJ, Anderton SM. Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4(+) T cells tolerized by peptide immunotherapy. Elife. 2014; 3. doi: 10.7554/eLife.03416
28. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008; 26: 677-704. doi: 10.1146/annurev. immunol.26.021607.090331
29. Liu C, Jiang J, Gao L, Hu X, Wang F, Shen Y, Yu G, Zhao Z, Zhang X. A Promoter Region Polymorphism in PDCD-1 Gene Is Associated with Risk of Rheumatoid Arthritis in the Han Chinese Population of Southeastern China. Int J Genomics. 2014; 2014: 247637. doi: 10.1155/2014/247637
30. Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, Cammer M, Chen L, Zhang ZY, Edidin MA, Nathenson SG, Almo SC. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004; 20: 337-347
31. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001; 98: 13866-13871
32. Unkeless JC, Jin J. Inhibitory receptors, ITIM sequences and phosphatases. Curr Opin Immunol. 1997; 9: 338-343
33. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ. A family of cytokine-inducible inhibitors of signalling. Nature. 1997; 387: 917-921
34. 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. doi: 10.1016/j.molmed.2014.10.009
35. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, Kwon ED. PD-1 is expressed by tumorinfiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007; 13: 1757-1761
36. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E, Chapuy B, Takeyama K, Neuberg D, Golub TR, Kutok JL, Shipp MA. 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. doi: 10.1182/blood-2010-05-282780
37. Koh YW, Jeon YK, Yoon DH, Suh C, Huh J. Programmed death 1 expression in the peritumoral microenvironment is associated with a poorer prognosis in classical Hodgkin lymphoma. Tumour Biol. 2016; 37: 7507-7514. doi: 10.1007/s13277-015-4622-5
38. Zhang Y, Kang S, Shen J, He J, Jiang L, Wang W, Guo Z, Peng G, Chen G, He J, Liang W. Prognostic significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1) Expression in epithelial-originated cancer: a meta-analysis. Medicine (Baltimore). 2015; 94: e515. doi: 10.1097/MD.0000000000000515
39. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996; 8: 765-772
40. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008; 8: 467-477. doi: 10.1038/nri2326
41. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA. Tumor antigenspecific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009; 114: 1537-1544. doi: 10.1182/blood-2008-12-195792
42. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, Shrikant P, Old LJ, Odunsi K. 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 U S A. 2010;107: 7875-7880. doi: 10.1073/pnas.1003345107
43. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015; 212: 139-148. doi: 10.1084/jem.20140559
44. 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. doi: 10.1002/jso.23281
45. Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MA, Intlekofer AM, Boss JM, Reiner SL, Weinmann AS, Wherry EJ. 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. doi: 10.1038/ni.2046
46. Li C, Li W, Xiao J, Jiao S, Teng F, Xue S, Zhang C, Sheng C, Leng Q, Rudd CE, Wei B, Wang H. ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8+ cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy. EMBO Mol Med. 2015; 7: 754-769. doi: 10.15252/emmm.201404578
47. Lu P, Youngblood BA, Austin JW, Mohammed AU, Butler R, Ahmed R, Boss JM. Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection. J Exp Med. 2014; 211: 515-527. doi: 10.1084/jem.20130208
48. 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 U S A. 2012. 109: 15419-15424
49. Austin JW, Lu P, Majumder P, Ahmed R, Boss JM. STAT3, STAT4, NFATc1, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells. J Immunol. 2014; 192: 4876-4886. doi: 10.4049/jimmunol.1302750
50. Bally AP, Lu P, Tang Y, Austin JW, Scharer CD, Ahmed R, Boss JM. NF-kappaB regulates PD-1 expression in macrophages. J Immunol. 2015; 194: 4545-4554. doi: 10.4049/jimmunol.1402550
51. Liu J, Kang H, Raab M, da Silva AJ, Kraeft SK, Rudd CE. FYB (FYN binding protein) serves as a binding partner for lymphoid protein and FYN kinase substrate SKAP55 and a SKAP55-related protein in T cells. Proc Natl Acad Sci U S A. 1998; 95: 8779-8784
52. Marie-Cardine A, Hendricks-Taylor LR, Boerth NJ, Zhao H, Schraven B, Koretzky GA. Molecular interaction between the Fyn-associated protein SKAP55 and the SLP-76-associated phosphoprotein SLAP-130. J Biol Chem. 1998; 40: 25789-25795
53. Massari F, Santoni M, Ciccarese C, Santini D, Alfieri S, Martignoni G, Brunelli M, Piva F, Berardi R, Montironi R, Porta C, Cascinu S, Tortora G. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev. 2015; 41: 114-121. doi: 10.1016/j. ctrv.2014.12.013
54. O'Shea JJ, Murray PJ. Murray, Cytokine signaling modules in inflammatory responses. Immunity. 2008;28: 477-487. doi: 10.1016/j.immuni.2008.03.002
55. Ozao-Choy J, Ma G, Kao J, Wang GX, Meseck M, Sung M, Schwartz M, Divino CM, Pan PY, Chen SH. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 2009; 69: 2514-2522. doi: 10.1158/0008-5472.CAN-08-4709
56. Rekik R, Belhadj Hmida N, Ben Hmid A, Zamali I, Kammoun N, Ben Ahmed M. PD-1 induction through TCR activation is partially regulated by endogenous TGFbeta. Cell Mol Immunol. 2015; 12: 648-649. doi: 10.1038/cmi.2014.104
57. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005; 25: 9543-9553
58. Sanmamed MF, Chen L. Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J. 2014; 20: 256-261. doi: 10.1097/PPO.0000000000000061
59. Bellmunt J, Mullane SA, Werner L, Fay AP, Callea M, Leow JJ, Taplin ME, Choueiri TK, Hodi FS, Freeman GJ, Signoretti S. Association of PD-L1 expression on tumorinfiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Ann Oncol. 2015; 26: 812-817. doi: 10.1093/annonc/mdv009
60. Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999; 5: 1365-1369
61. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010; 116: 1757-1766. doi: 10.1002/cncr.24899
62. Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant. 2012; 12: 2575-2587. doi: 10.1111/j.1600-6143.2012.04224.x
63. 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. doi: 10.2147/PGPM.S53163. eCollection 2014
64. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012; 24: 207-212. doi: 10.1016/j. coi.2011.12.009
65. Stanciu LA, Bellettato CM, Laza-Stanca V, Coyle AJ, Papi A, Johnston SL. Expression of programmed death-1 ligand (PD-L) 1, PD-L2, B7-H3, and inducible costimulator ligand on human respiratory tract epithelial cells and regulation by respiratory syncytial virus and type 1 and 2 cytokines. J Infect Dis. 2006; 193: 404-412
66. Kan-o K, Matsumoto K, Asai-Tajiri Y, Fukuyama S, Hamano S, Seki N, Nakanishi Y, Inoue H. PI3K-delta mediates double-stranded RNA-induced upregulation of B7-H1 in BEAS-2B airway epithelial cells. Biochem Biophys Res Commun. 2013; 435: 195-201. doi: 10.1016/j. bbrc.2013.04.082
67. Chen J, Feng Y, Lu L, Wang H, Dai L, Li Y, Zhang P. Interferon-gamma-induced PD-L1 surface expression on human oral squamous carcinoma via PKD2 signal pathway. Immunobiology. 2012; 217: 385-393. doi: 10.1016/j. imbio.2011.10.016
68. Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M. IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer. 2015; 112: 1501-1509. doi: 10.1038/bjc.2015.101
69. Krönig H, Kremmler L, Haller B, Englert C, Peschel C, Andreesen R, Blank CU. Interferon-induced programmed death-ligand 1 (PD-L1/B7-H1) expression increases on human acute myeloid leukemia blast cells during treatment. Eur J Haematol. 2014; 92: 195-203. doi: 10.1111/ejh.12228
70. Bellucci R, Martin A, Bommarito D, Wang K, Hansen SH, Freeman GJ, Ritz J. Interferon-gamma-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression. Oncoimmunology. 2015; 4: e1008824
71. Maine CJ, Aziz NH, Chatterjee J, Hayford C, Brewig N, Whilding L, George AJ, Ghaem-Maghami S. Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer. Cancer Immunol Immunother. 2014; 63: 215-224. doi: 10.1007/s00262-013-1503-x
72. Chen N, Fang W, Zhan J, Hong S, Tang Y, Kang S, Zhang Y, He X, Zhou T, Qin T, Huang Y, Yi X, Zhang L. Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation. J Thorac Oncol. 2015; 10: 910-923. doi: 10.1097/JTO.0000000000000500
73. Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, Mikse OR, Cherniack AD, Beauchamp EM, Pugh TJ, Wilkerson MD, Fecci PE, Butaney M, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013; 3: 1355-1363. doi: 10.1158/2159-8290.CD-13-0310
74. Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, Harada T, Matsumoto K, Takayama K, Takamori S, Kage M, Hoshino T, Nakanishi Y, et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in nonsmall cell lung cancer. Clin Cancer Res. 2015; 21: 4014-4021 doi: 10.1158/1078-0432.CCR-15-0016
75. Balan M, Miery Teran E, Waaga-Gasser AM, Gasser M, Choueiri TK, Freeman G, Pal S. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J Biol Chem. 2015; 290: 8110-8120. doi: 10.1074/jbc.M114.612689
76. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007; 13: 84-88
77. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014; 211: 781-790. doi: 10.1084/jem.20131916
78. Scharenberg AM, Humphries LA, Rawlings DJ. Calcium signalling and cell-fate choice in B cells. Nat Rev Immunol. 2007; 7: 778-789
79. Mashima R, Hishida Y, Tezuka T, Yamanashi Y. The roles of Dok family adapters in immunoreceptor signaling. Immunol Rev. 2009; 232: 273-285. doi: 10.1111/j.1600-065X.2009.00844.x
80. Ng CH, Xu S, Lam KP. Dok-3 plays a nonredundant role in negative regulation of B-cell activation. Blood. 2007; 110: 259-266
81. Stork B, Neumann K, Goldbeck I, Alers S, Kähne T, Naumann M, Engelke M, Wienands J. Subcellular localization of Grb2 by the adaptor protein Dok-3 restricts the intensity of Ca2+ signaling in B cells. EMBO J. 2007; 26: 1140-1149
82. Ou X, Xu S, Li YF1, Lam KP. Adaptor protein DOK3 promotes plasma cell differentiation by regulating the expression of programmed cell death 1 ligands. Proc Natl Acad Sci U S A. 2014; 111: 11431-11436. doi: 10.1073/pnas.1400539111
83. Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, Garcia C, Wu Y, Kuhne M, Srinivasan M, Singh S, Wong S, Garner N, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014; 2: 846-856. doi: 10.1158/2326-6066.CIR-14-0040
84. Xiao Y, Yu S, Zhu B, Bedoret D, Bu X, Francisco LM, Hua P, Duke-Cohan JS, Umetsu DT, Sharpe AH, DeKruyff RH, Freeman GJ. RGMb is a novel binding partner for PDL2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med. 2014; 211: 943-959. doi: 10.1084/jem.20130790
85. Chikuma S, Terawaki S, Hayashi T, Nabeshima R, Yoshida T, Shibayama S, Okazaki T, Honjo T. PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J Immunol. 2009; 182: 6682-6689. doi: 10.4049/jimmunol.0900080
86. Bishop KD, Harris JE, Mordes JP, Greiner DL, Rossini AA, Czech MP, Phillips NE. Depletion of the programmed death-1 receptor completely reverses established clonal anergy in CD4(+) T lymphocytes via an interleukin-2-dependent mechanism. Cell Immunol. 2009; 256: 86-91. doi: 10.1016/j.cellimm.2009.01.008
87. Dai S, Jia R, Zhang X, Fang Q, Huang L. The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol. 2014; 290: 72-79. doi: 10.1016/j.cellimm.2014.05.006
88. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000; 192: 1027-1034
89. Hersey P, Gowrishankar K. Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Future Oncol. 2015; 11: 133-140. doi: 10.2217/fon.14.205
90. Zhao S, Li F, Leak RK, Chen J, Hu X. Regulation of neuroinflammation through programed death-1/programed death ligand signaling in neurological disorders. Front Cell Neurosci. 2014; 8: 271. doi: 10.3389/fncel.2014.00271
91. Atefi M, Avramis E, Lassen A, Wong DJ, Robert L, Foulad D, Cerniglia M, Titz B, Chodon T, Graeber TG, Comin-Anduix B, Ribas A. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin Cancer Res. 2014; 20: 3446-3457. doi: 10.1158/1078-0432.CCR-13-2797
92. Wei F, Zhong S, Ma Z, Kong H, Medvec A, Ahmed R, Freeman GJ, Krogsgaard M, Riley JL. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci U S A. 2013; 110: E2480-2489. doi: 10.1073/pnas.1305394110
93. Bachegowda LS, Barta SK. Genetic and molecular targets in lymphoma: implications for prognosis and treatment. Future Oncol. 2014; 10: 2509-2528. doi: 10.2217/fon.14.112
94. Lu B, Chen L, Liu L, Zhu Y, Wu C, Jiang J, Zhang X. T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract. Immunol Res. 2011; 50: 269-275. doi: 10.1007/s12026-011-8227-9
95. Gianchecchi E, Delfino DV, Fierabracci A. Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity. Autoimmun Rev. 2013; 12: 1091-1100. doi: 10.1016/j.autrev.2013.05.003
96. Bryan LJ, Gordon LI. Blocking tumor escape in hematologic malignancies: the anti-PD-1 strategy. Blood Rev. 2015; 29: 25-32. doi: 10.1016/j.blre.2014.09.004
97. Jandus C, Bioley G, Speiser DE, Romero P. Selective accumulation of differentiated FOXP3(+) CD4 (+) T cells in metastatic tumor lesions from melanoma patients compared to peripheral blood. Cancer Immunol Immunother. 2008; 57: 1795-1805. doi: 10.1007/s00262-008-0507-4
98. Zheng Y, Zha Y, Driessens G, Locke F, Gajewski TF. Transcriptional regulator early growth response gene 2 (Egr2) is required for T cell anergy in vitro and in vivo. J Exp Med. 2012; 209: 2157-2163. doi: 10.1084/jem.20120342
99. Qian N, Gao L, Dong L, Liu H, Fu J, Meng D, Gao X, Zhang J, Gao Y3, Song H. Construction, expression, purification, and characterization of a dual-targeting PD-1/VEGF-A fusion protein (P-V). Protein Expr Purif. 2015; 109: 1-6. doi: 10.1016/j.pep.2015.01.004
100. Boussiotis, V.A., P. Chatterjee, and L. Li, Biochemical signaling of PD-1 on T cells and its functional implications. Cancer J, 2014. 20: 265-271. doi: 10.1097/PPO.0000000000000059
101. Li J, Jie HB, Lei Y, Gildener-Leapman N, Trivedi S, Green T, Kane LP, Ferris RL. PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res. 2015; 75: 508-518. doi: 10.1158/0008-5472.CAN-14-1215
102. Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja MK, Yu XZ, Dong C. T-cell tolerance or function is determined by combinatorial costimulatory signals. EMBO J. 2006; 25: 2623-2633
103. Stolarczyk E, Lord GM, Howard JK. The immune cell transcription factor T-bet: A novel metabolic regulator. Adipocyte. 2014; 3: 58-62. doi: 10.4161/adip.26220
104. Chen LJ, Sun J, Wu HY, Zhou SM, Tan Y, Tan M, Shan BE, Lu BF, Zhang XG. B7-H4 expression associates with cancer progression and predicts patient's survival in human esophageal squamous cell carcinoma. Cancer Immunol Immunother. 2011; 60: 1047-1055. doi: 10.1007/s00262-011-1017-3
105. Patsoukis N, Sari D, Boussiotis VA. PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. Cell Cycle. 2012; 11: 4305-4309. doi: 10.4161/cc.22135
106. Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 2012; 5: ra46. doi: 10.1126/scisignal.2002796
107. Kim JW, Nam KH, Ahn SH, Park do J, Kim HH, Kim SH, Chang H, Lee JO, Kim YJ, Lee HS, Kim JH, Bang SM, Lee JS, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer. 2016; 19: 42-52. doi: 10.1007/s10120-014-0440-5
108. Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B, Majdic O, Gajewski TF, Theobald M, Andreesen R, Mackensen A. Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer. 2006; 119: 317-327
109. Schlößer HA, Theurich S, Shimabukuro-Vornhagen A, Holtick U, Stippel DL, von Bergwelt-Baildon M. Overcoming tumor-mediated immunosuppression. Immunotherapy., 2014; 6: 973-988. doi: 10.2217/imt.14.58
110. Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin Cancer Res. 2011; 17: 6985-6991. doi: 10.1158/1078-0432.CCR-11-1331
111. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009; 206: 3015-3029. doi: 10.1084/jem.20090847
112. Chen X, Fosco D, Kline DE, Meng L, Nishi S, Savage PA, Kline J. PD-1 regulates extrathymic regulatory T-cell differentiation. Eur J Immunol. 2014; 44: 2603-2616. doi: 10.1002/eji.201344423
113. Zhong A, Pan X, Shi M. Expression of PD-1 by CD4(+) CD25(+)CD127(low) Treg cells in the peripheral blood of lung cancer patients. Onco Targets Ther. 2015; 8: 1831-1833 doi: 10.2147/OTT.S90538
114. Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S. FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy. BMC Cancer. 2008; 8: 57. doi: 10.1186/1471-2407-8-57
115. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12: 252-264. doi: 10.1038/nrc3239
116. Tykodi SS. PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence. Onco Targets Ther. 2014; 7: 1349-1359. doi: 10.2147/OTT.S48443
117. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, Sander C, Kirkwood JM, Chen TH, Maurer M, Korman AJ, Zarour HM. TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest. 2015; 125: 2046-2058. doi: 10.1172/JCI80445
118. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM. 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. doi: 10.1084/jem.20100637
119. Zheng W, Xiao H, Liu H, Zhou Y. Expression of programmed death 1 is correlated with progression of osteosarcoma. APMIS. 2015; 123: 102-107. doi: 10.1111/apm.12311
120. van Dam LS, de Zwart VM, Meyer-Wentrup FA. The role of programmed cell death-1 (PD-1) and its ligands in pediatric cancer. Pediatr Blood Cancer. 2015; 62: 190-197. doi: 10.1002/pbc.25284
121. Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2005; 17: 133-144
122. Shiner EK, Holbrook BC, Alexander-Miller MA. CD4+ T cell subset differentiation and avidity setpoint are dictated by the interplay of cytokine and antigen mediated signals. PLoS One. 2014; 9: e100175. doi: 10.1371/journal. pone.0100175
123. Dulos J, Carven GJ, van Boxtel SJ, Evers S, Driessen-Engels LJ, Hobo W, Gorecka MA, de Haan AF, Mulders P, Punt CJ, Jacobs JF, Schalken JA, Oosterwijk E, et al. PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. J Immunother. 2012; 35: 169-178. doi: 10.1097/CJI.0b013e318247a4e7
124. Mangsbo SM, Sandin LC, Anger K, Korman AJ, Loskog A, Tötterman TH. Enhanced tumor eradication by combining CTLA-4 or PD-1 blockade with CpG therapy. J Immunother. 2010; 33: 225-235. doi: 10.1097/CJI.0b013e3181c01fcb
125. Meng X, Huang Z, Teng F, Xing L, Yu J. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat Rev. 2015; 41: 868-876. doi: 10.1016/j.ctrv.2015.11.001
126. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, et al. Anti-programmeddeath-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384: 1109-1117. doi: 10.1016/S0140-6736(14)60958-2
127. Lee SM, Chow LQ. A new addition to the PD-1 checkpoint inhibitors for non-small cell lung cancer-the anti-PDL1 antibody-MEDI4736. Transl Lung Cancer Res. 2014; 3: 408-410. doi: 10.3978/j.issn.2218-6751.2014.11.10
128. Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, et al. Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma. JAMA. 2016; 315: 1600-1609. doi: 10.1001/jama.2016.4059
129. Swaika A, Hammond WA, Joseph RW. Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol Immunol. 2015; 67: 4-17. doi: 10.1016/j. molimm.2015.02.009
130. Philips GK, Atkins M. Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. Int Immunol. 2015; 27: 39-46. doi: 10.1093/intimm/dxu095
131. Hardy B, Yampolski I, Kovjazin R, Galli M, Novogrodsky A. A monoclonal antibody against a human B lymphoblastoid cell line induces tumor regression in mice. Cancer Res. 1994; 54: 5793-5796
132. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A. 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. doi: 10.1158/1078-0432.CCR-07-4079
133. Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, Kaminski MS, Holland HK, Winter JN, Mason JR, Fay JW, Rizzieri DA, Hosing CM, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013. 31: 4199-4206. doi: 10.1200/JCO.2012.48.3685
134. Kim JW, Eder JP. Prospects for targeting PD-1 and PD-L1 in various tumor types. Oncology (Williston Park). 2014; 28 3: 15-28
135. Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol. 2015; 23: 32-38. doi: 10.1016/j. coph.2015.05.011
136. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366: 2455-2465. doi: 10.1056/NEJMoa1200694
137. Langer CJ. Emerging immunotherapies in the treatment of non-small cell lung cancer (NSCLC): the role of immune checkpoint inhibitors. Am J Clin Oncol. 2015. 38: 422-430. doi: 10.1097/COC.0000000000000059
138. Zielinski CC. A phase I study of MEDI4736, NNTPD-L1 antibody in patients with advanced solid tumors. Transl Lung Cancer Res. 2014; 3: 406-407. oi: 10.3978/j. issn.2218-6751.2014.08.07
139. Yun S, Vincelette ND, Green MR, Wahner Hendrickson AE, Abraham I. Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials. Cancer Med. 2016; 5: 1481-1491. doi: 10.1002/cam4.732
140. Valsecchi ME. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015; 373: 1270. doi: 10.1056/NEJMc1509660#SA1