Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PDL1 blockade

Oncotarget

Volumn 8, Issue 66, 2017, Pages 110693-110707

  Bai, Jie ^a   Gao, Zhitao ^a   Li, Xiang ^a   Dong, Liang ^a   Han, Weidong ^a   Nie, Jing ^a  

^a CHINESE PLA GENERAL HOSPITAL   (China)

Author keywords

Epigenetic; PD 1; PD L1; Resistance; Tumor microenvironment

Indexed keywords

ANTINEOPLASTIC AGENT; PROGRAMMED DEATH 1 LIGAND 1; TUMOR ANTIGEN;

ANTIGEN PRESENTATION; CANCER CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER RESISTANCE; DRUG EFFICACY; EPIGENETICS; HUMAN; MALIGNANT NEOPLASM; NONHUMAN; PROTEIN EXPRESSION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; TRANSCRIPTOMICS; TUMOR MICROENVIRONMENT;

EID: 85038115717     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.22690     Document Type: Review

References (137)

1. Bretscher P, Cohn M. A theory of self-nonself discrimination. Science. 1970; 169: 1042-9.
2. Bretscher PA. A two-step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci U S A. 1999; 96: 185-90.
3. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995; 3: 541-7.
4. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995; 270: 985-8.
5. 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: 141-51.
6. 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: 319-22. https:// doi.org/10.1126/science.291.5502.319.
7. Karandikar NJ, Vanderlugt CL, Bluestone JA, Miller SD. Targeting the B7/CD28:CTLA-4 costimulatory system in CNS autoimmune disease. J Neuroimmunol. 1998; 89: 10-8.
8. Oosterwegel MA, Greenwald RJ, Mandelbrot DA, Lorsbach RB, Sharpe AH. CTLA-4 and T cell activation. Curr Opin Immunol. 1999; 11: 294-300.
9. Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol. 2001; 19: 225-52. https://doi.org/10.1146/annurev.immunol.19.1.225.
10. Sansom DM. CD28, CTLA-4 and their ligands: who does what and to whom? Immunology. 2000; 101: 169-77.
11. 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: 565-94. https://doi. org/10.1146/annurev.immunol.19.1.565.
12. Chen L, Linsley PS, Hellstrom KE. Costimulation of T cells for tumor immunity. Immunol Today. 1993; 14: 483-6. https://doi.org/10.1016/0167-5699(93)90262-j.
13. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996; 271: 1734-6.
14. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363: 711-23. https://doi.org/10.1056/NEJMoa1003466.
15. 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: 2443-54. https://doi.org/10.1056/NEJMoa1200690.
16. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015; 372: 2521-32. https://doi.org/10.1056/NEJMoa1503093.
17. Valsecchi ME. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373: 1270. https://doi.org/10.1056/NEJMc1509660#SA1.
18. 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: 765-72.
19. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, Shin T, Tsuchiya H, Pardoll DM, Okumura K, Azuma M, Yagita H. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol. 2002; 169: 5538-45.
20. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008; 26: 677-704. https://doi.org/10.1146/annurev. immunol.26.021607.090331.
21. Finger LR, Pu J, Wasserman R, Vibhakar R, Louie E, Hardy RR, Burrows PD, Billips LG. The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors. Gene. 1997; 197: 177-87.
22. Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O'Shea MA, Fauci AS. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008; 181: 6738-46.
23. Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J Immunol. 2008; 181: 4832-9.
24. Terawaki S, Chikuma S, Shibayama S, Hayashi T, Yoshida T, Okazaki T, Honjo T. IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol. 2011; 186: 2772-9. https://doi.org/10.4049/jimmunol.1003208.
25. Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity. 2014; 41: 802-14. https://doi. org/10.1016/j.immuni.2014.10.013.
26. Mathieu M, Cotta-Grand N, Daudelin JF, Thebault P, Labrecque N. Notch signaling regulates PD-1 expression during CD8(+) T-cell activation. Immunol Cell Biol. 2013; 91: 82-8. https://doi.org/10.1038/icb.2012.53.
27. 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: 663-71. https:// doi.org/10.1038/ni.2046.
28. Watanabe T, Bertoletti A, Tanoto TA. PD-1/PD-L1 pathway and T-cell exhaustion in chronic hepatitis virus infection. J Viral Hepat. 2010; 17: 453-8. https://doi. org/10.1111/j.1365-2893.2010.01313.x.
29. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006; 443: 350-4. https:// doi.org/10.1038/nature05115.
30. Buermann A, Romermann D, Baars W, Hundrieser J, Klempnauer J, Schwinzer R. Inhibition of B-cell activation and antibody production by triggering inhibitory signals via the PD-1/PD-ligand pathway. Xenotransplantation. 2016; 23: 347-56. https://doi.org/10.1111/xen.12261.
31. Xiao X, Lao XM, Chen MM, Liu RX, Wei Y, Ouyang FZ, Chen DP, Zhao XY, Zhao Q, Li XF, Liu CL, Zheng L, Kuang DM. PD-1hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov. 2016; 6: 546-59. https://doi. org/10.1158/2159-8290.cd-15-1408.
32. Cho HY, Lee SW, Seo SK, Choi IW, Choi I, Lee SW. Interferon-sensitive response element (ISRE) is mainly responsible for IFN-alpha-induced upregulation of programmed death-1 (PD-1) in macrophages. Biochim Biophys Acta. 2008; 1779: 811-9. https://doi.org/10.1016/j. bbagrm.2008.08.003.
33. Lazar-Molnar E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci U S A. 2008; 105: 10483-8. https://doi. org/10.1073/pnas.0804453105.
34. Lin DY, Tanaka Y, Iwasaki M, Gittis AG, Su HP, Mikami B, Okazaki T, Honjo T, Minato N, Garboczi DN. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci U S A. 2008; 105: 3011-6. https://doi.org/10.1073/ pnas.0712278105.
35. Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL. PD-L2 expression extends beyond dendritic cells/ macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol. 2007; 37: 2405-10. https://doi.org/10.1002/eji.200737461.
36. 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: 1027-34.
37. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001; 2: 261-8. https://doi.org/10.1038/85330.
38. 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: 1365-9. https:// doi.org/10.1038/70932.
39. Selenko-Gebauer N, Majdic O, Szekeres A, Hofler G, Guthann E, Korthauer U, Zlabinger G, Steinberger P, Pickl WF, Stockinger H, Knapp W, Stockl J. B7-H1 (programmed death-1 ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J Immunol. 2003; 170: 3637-44.
40. Currie AJ, Prosser A, McDonnell A, Cleaver AL, Robinson BW, Freeman GJ, van der Most RG. Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation. J Immunol. 2009; 183: 7898-908. https:// doi.org/10.4049/jimmunol.0901060.
41. Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009; 206: 1327-37. https://doi.org/10.1084/jem.20082173.
42. Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009; 114: 1545-52. https://doi.org/10.1182/blood-2009-03-206672.
43. Youngblood B, Oestreich KJ, Ha SJ, Duraiswamy J, Akondy RS, West EE, Wei Z, Lu P, Austin JW, Riley JL, Boss JM, Ahmed R. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells. Immunity. 2011; 35: 400-12. https://doi.org/10.1016/j. immuni.2011.06.015.
44. Ahn E, Youngblood B, Lee J, Lee J, Sarkar S, Ahmed R. Demethylation of the PD-1 promoter is imprinted during the effector phase of CD8 T cell exhaustion. J Virol. 2016; 90: 8934-46. https://doi.org/10.1128/jvi.00798-16.
45. Youngblood B, Noto A, Porichis F, Akondy RS, Ndhlovu ZM, Austin JW, Bordi R, Procopio FA, Miura T, Allen TM, Sidney J, Sette A, Walker BD, et al. Cutting edge: prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. J Immunol. 2013; 191: 540-4. https://doi.org/10.4049/ jimmunol.1203161.
46. Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, Hanna J, Lodato MA, Frampton GM, Sharp PA, Boyer LA, Young RA, Jaenisch R. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107: 21931-6. https://doi.org/10.1073/pnas.1016071107.
47. 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: e03416. https://doi.org/10.7554/eLife.03416.
48. 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: 515-27. https://doi.org/10.1084/jem.20130208.
49. Li Q, Johnston N, Zheng X, Wang H, Zhang X, Gao D, Min W. miR-28 modulates exhaustive differentiation of T cells through silencing programmed cell death-1 and regulating cytokine secretion. Oncotarget. 2016; 7: 53735-50. https:// doi.org/10.18632/oncotarget.10731.
50. Wei J, Nduom EK, Kong LY, Hashimoto Y, Xu S, Gabrusiewicz K, Ling X, Huang N, Qiao W, Zhou S, Ivan C, Fuller GN, Gilbert MR, et al. MiR-138 exerts antiglioma efficacy by targeting immune checkpoints. Neuro Oncol. 2016; 18: 639-48. https://doi.org/10.1093/neuonc/ nov292.
51. Zhang G, Li N, Li Z, Zhu Q, Li F, Yang C, Han Q, Lv Y, Zhou Z, Liu Z. microRNA-4717 differentially interacts with its polymorphic target in the PD1 3' untranslated region: a mechanism for regulating PD-1 expression and function in HBV-associated liver diseases. Oncotarget. 2015; 6: 18933-44. https://doi.org/10.18632/oncotarget.3662.
52. Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004; 574: 37-41. https://doi.org/10.1016/j.febslet.2004.07.083.
53. 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. https://doi. org/10.1126/scisignal.2002796.
54. 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: 9543-53. https://doi.org/10.1128/ mcb.25.21.9543-9553.2005.
55. Vazquez F, Ramaswamy S, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol. 2000; 20: 5010-8.
56. Torres J, Pulido R. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem. 2001; 276: 993-8. https://doi. org/10.1074/jbc.M009134200.
57. Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol Cell Biol. 2013; 33: 3091-8. https://doi.org/10.1128/ mcb.00319-13.
58. Bivona TG, Perez De Castro I, Ahearn IM, Grana TM, Chiu VK, Lockyer PJ, Cullen PJ, Pellicer A, Cox AD, Philips MR. Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature. 2003; 424: 694-8. https://doi.org/10.1038/nature01806.
59. 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: 13866-71. https://doi.org/10.1073/ pnas.231486598.
60. Chen DS, Irving BA, Hodi FS. Molecular pathways: nextgeneration immunotherapy--inhibiting programmed deathligand 1 and programmed death-1. Clin Cancer Res. 2012; 18: 6580-7. https://doi.org/10.1158/1078-0432.ccr-12-1362.
61. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015; 348: 56-61. https://doi.org/10.1126/ science.aaa8172.
62. 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: 134-44. https://doi.org/10.1056/ NEJMoa1305133.
63. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015; 372: 311-9. https://doi.org/10.1056/NEJMoa1411087.
64. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015; 160: 48-61. https://doi.org/10.1016/j.cell.2014.12.033.
65. Lastwika KJ, Wilson W 3rd, Li QK, Norris J, Xu H, Ghazarian SR, Kitagawa H, Kawabata S, Taube JM, Yao S, Liu LN, Gills JJ, Dennis PA. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res. 2016; 76: 227-38. https://doi.org/10.1158/0008-5472.can-14-3362.
66. 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: 1355-63. https://doi.org/10.1158/2159-8290.cd-13-0310.
67. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, Gouw AM, Baylot V, Gutgemann I, Eilers M, Felsher DW. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016; 352: 227-31. https://doi. org/10.1126/science.aac9935.
68. Dorand RD, Nthale J, Myers JT, Barkauskas DS, Avril S, Chirieleison SM, Pareek TK, Abbott DW, Stearns DS, Letterio JJ, Huang AY, Petrosiute A. Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Science. 2016; 353: 399-403. https://doi. org/10.1126/science.aae0477.
69. Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, Maeda T, Nagata Y, Kitanaka A, Mizuno S, Tanaka H, Chiba K, Ito S, et al. Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature. 2016; 534: 402-6. https://doi.org/10.1038/nature18294.
70. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ, Mulder GE, Toebes M, Vesely MD, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014; 515: 577-81. https://doi. org/10.1038/nature13988.
71. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015; 348: 69-74. https://doi. org/10.1126/science.aaa4971.
72. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348: 124-8. https://doi.org/10.1126/science.aaa1348.
73. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, van Dijk LJ, Behjati S, Hilkmann H, El Atmioui D, Nieuwland M, Stratton MR, Kerkhoven RM, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013; 31: e439-42. https://doi.org/10.1200/ jco.2012.47.7521.
74. Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK, Hundal J, Wendl MC, Demeter R, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012; 482: 400-4. https:// doi.org/10.1038/nature10755.
75. Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, White J, Zhang T, Adleff V, Phallen J, Wali N, Hruban C, Guthrie VB, Rodgers K, et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 2017; 7: 264-76. https://doi.org/10.1158/2159-8290.CD-16-0828.
76. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol. 2000; 74: 181-273.
77. Sucker A, Zhao F, Real B, Heeke C, Bielefeld N, Mabetaen S, Horn S, Moll I, Maltaner R, Horn PA, Schilling B, Sabbatino F, Lennerz V, et al. Genetic evolution of T-cell resistance in the course of melanoma progression. Clin Cancer Res. 2014; 20: 6593-604. https://doi. org/10.1158/1078-0432.ccr-14-0567.
78. Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst. 1996; 88: 100-8.
79. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, Xu C, McKenzie JA, Zhang C, Liang X, Williams LJ, Deng W, Chen G, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016; 6: 202-16. https://doi.org/10.1158/2159-8290.cd-15-0283.
80. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic betacatenin signalling prevents anti-tumour immunity. Nature. 2015; 523: 231-5. https://doi.org/10.1038/nature14404.
81. Gao J, Shi LZ, Zhao H, Chen J, Xiong L, He Q, Chen T, Roszik J, Bernatchez C, Woodman SE, Chen PL, Hwu P, Allison JP, et al. Loss of IFN-gamma pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell. 2016; 167: 397-404.e9. https://doi. org/10.1016/j.cell.2016.08.069.
82. Ribas A. Adaptive immune resistance: how cancer protects from immune attack. Cancer Discov. 2015; 5: 915-9. https:// doi.org/10.1158/2159-8290.cd-15-0563.
83. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, Saco J, Homet Moreno B, Mezzadra R, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016; 375: 819-29. https://doi.org/10.1056/NEJMoa1604958.
84. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001; 410: 1107-11. https://doi. org/10.1038/35074122.
85. Benci JL, Xu B, Qiu Y, Wu TJ, Dada H, Twyman-Saint Victor C, Cucolo L, Lee DS, Pauken KE, Huang AC, Gangadhar TC, Amaravadi RK, Schuchter LM, et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell. 2016; 167: 1540-54.e12. https://doi.org/10.1016/j.cell.2016.11.022.
86. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994; 264: 1415-21.
87. Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr Opin Immunol. 2015; 33: 23-35. https://doi.org/10.1016/j. coi.2015.01.006.
88. Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, Grasso CS, Hugo W, Sandoval S, Torrejon DY, Palaskas N, Rodriguez GA, Parisi G, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017; 7: 188-201. https://doi. org/10.1158/2159-8290.cd-16-1223.
89. Liu C, Peng W, Xu C, Lou Y, Zhang M, Wargo JA, Chen JQ, Li HS, Watowich SS, Yang Y, Tompers Frederick D, Cooper ZA, Mbofung RM, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013; 19: 393-403. https://doi.org/10.1158/1078-0432. CCR-12-1626.
90. Donia M, Fagone P, Nicoletti F, Andersen RS, Hogdall E, Straten PT, Andersen MH, Svane IM. BRAF inhibition improves tumor recognition by the immune system: potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer. Oncoimmunology. 2012; 1: 1476-83. https://doi. org/10.4161/onci.21940.
91. Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, Moriceau G, Hong A, Dahlman KB, Johnson DB, Sosman JA, Ribas A, Lo RS. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell. 2015; 162: 1271-85. https://doi.org/10.1016/j.cell.2015.07.061.
92. Deken MA, Gadiot J, Jordanova ES, Lacroix R, van Gool M, Kroon P, Pineda C, Geukes Foppen MH, Scolyer R, Song JY, Verbrugge I, Hoeller C, Dummer R, et al. Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma. Oncoimmunology. 2016; 5: e1238557. https://doi.org/10.1080/21624 02x.2016.1238557.
93. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012; 21: 309-22. https://doi.org/10.1016/j. ccr.2012.02.022.
94. Blackburn SD, Shin H, Freeman GJ, Wherry EJ. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A. 2008; 105: 15016-21. https://doi.org/10.1073/pnas.0801497105.
95. Oida T, Zhang X, Goto M, Hachimura S, Totsuka M, Kaminogawa S, Weiner HL. CD4+CD25-T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-betadependent mechanism. J Immunol. 2003; 170: 2516-22.
96. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008; 133: 775-87. https://doi.org/10.1016/j.cell.2008.05.009.
97. Sundstedt A, O'Neill EJ, Nicolson KS, Wraith DC. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol. 2003; 170: 1240-8.
98. Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel). 2016; 4: E28. https://doi.org/10.3390/vaccines4030028.
99. Linehan DC, Goedegebuure PS. CD25+ CD4+ regulatory T-cells in cancer. Immunol Res. 2005; 32: 155-68. https:// doi.org/10.1385/ir:32:1-3:155.
100. Viehl CT, Moore TT, Liyanage UK, Frey DM, Ehlers JP, Eberlein TJ, Goedegebuure PS, Linehan DC. Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice. Ann Surg Oncol. 2006; 13: 1252-8. https://doi.org/10.1245/ s10434-006-9015-y.
101. Dyck L, Wilk MM, Raverdeau M, Misiak A, Boon L, Mills KH. Anti-PD-1 inhibits Foxp3+ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model. Cancer Immunol Immunother. 2016; 65: 1491-8. https://doi. org/10.1007/s00262-016-1906-6.
102. Yang L, Huang J, Ren X, Gorska AE, Chytil A, Aakre M, Carbone DP, Matrisian LM, Richmond A, Lin PC, Moses HL. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008; 13: 23-35. https:// doi.org/10.1016/j.ccr.2007.12.004.
103. Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A, Francescato S, Basso G, Zanovello P, Onicescu G, Garrett-Mayer E, Montero AJ, Bronte V, et al. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood. 2011; 118: 2254-65. https://doi. org/10.1182/blood-2010-12-325753.
104. Meyer C, Cagnon L, Costa-Nunes CM, Baumgaertner P, Montandon N, Leyvraz L, Michielin O, Romano E, Speiser DE. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother. 2014; 63: 247-57. https://doi.org/10.1007/s00262-013-1508-5.
105. De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature. 2016; 539: 443-7. https://doi.org/10.1038/nature20554.
106. Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature. 2016; 539: 437-42. https://doi.org/10.1038/nature19834.
107. Chanmee T, Ontong P, Konno K, Itano N. Tumorassociated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014; 6: 1670-90. https://doi.org/10.3390/cancers6031670.
108. Hu W, Li X, Zhang C, Yang Y, Jiang J, Wu C. Tumorassociated macrophages in cancers. Clin Transl Oncol. 2016; 18: 251-8. https://doi.org/10.1007/s12094-015-1373-0.
109. Fritz JM, Tennis MA, Orlicky DJ, Lin H, Ju C, Redente EF, Choo KS, Staab TA, Bouchard RJ, Merrick DT, Malkinson AM, Dwyer-Nield LD. Depletion of tumor-associated macrophages slows the growth of chemically induced mouse lung adenocarcinomas. Front Immunol. 2014; 5: 587. https://doi.org/10.3389/fimmu.2014.00587.
110. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014; 74: 5057-69. https://doi. org/10.1158/0008-5472.can-13-3723.
111. Lebrun JJ. The dual role of TGFbeta in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol. 2012; 2012: 381428. https://doi.org/10.5402/2012/381428.
112. Lin RL, Zhao LJ. Mechanistic basis and clinical relevance of the role of transforming growth factor-beta in cancer. Cancer Biol Med. 2015; 12: 385-93. https://doi. org/10.7497/j.issn.2095-3941.2015.0015.
113. Vanpouille-Box C, Diamond JM, Pilones KA, Zavadil J, Babb JS, Formenti SC, Barcellos-Hoff MH, Demaria S. TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 2015; 75: 2232-42. https://doi.org/10.1158/0008-5472.can-14-3511.
114. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, Kaplan RN, Mackall CL. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. 2014; 6: 237ra67. https://doi.org/10.1126/ scitranslmed.3007974.
115. Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013; 34: 137-43. https://doi.org/10.1016/j.it.2012.10.001.
116. Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol Immunother. 2014; 63: 721-35. https://doi.org/10.1007/ s00262-014-1549-4.
117. Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012; 72: 5435-40. https://doi. org/10.1158/0008-5472.can-12-0569.
118. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013; 210: 1389-402. https://doi.org/10.1084/jem.20130066.
119. Thommen DS, Schreiner J, Muller P, Herzig P, Roller A, Belousov A, Umana P, Pisa P, Klein C, Bacac M, Fischer OS, Moersig W, Savic Prince S, et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol Res. 2015; 3: 1344-55. https://doi. org/10.1158/2326-6066.cir-15-0097.
120. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H, Jones RE, Kulkarni MM, Kuraguchi M, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016; 7: 10501. https://doi.org/10.1038/ ncomms10501.
121. Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, Seja E, Lomeli S, Kong X, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016; 165: 35-44. https://doi. org/10.1016/j.cell.2016.02.065.
122. Karpf AR, Jones DA. Reactivating the expression of methylation silenced genes in human cancer. Oncogene. 2002; 21: 5496-503. https://doi.org/10.1038/sj.onc.1205602.
123. Kim HJ, Bae SC. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res. 2011; 3: 166-79.
124. Heninger E, Krueger TE, Lang JM. Augmenting antitumor immune responses with epigenetic modifying agents. Front Immunol. 2015; 6: 29. https://doi.org/10.3389/ fimmu.2015.00029.
125. Wang LX, Mei ZY, Zhou JH, Yao YS, Li YH, Xu YH, Li JX, Gao XN, Zhou MH, Jiang MM, Gao L, Ding Y, Lu XC, et al. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. PLoS One. 2013; 8: e62924. https://doi.org/10.1371/journal.pone.0062924.
126. Li X, Zhang Y, Chen M, Mei Q, Liu Y, Feng KC, Jia H, Dong L, Shi L, Liu L, Nie J, Han W. Increased IFN-gamma+ T cells are responsible for the clinical responses of low-dose DNA demethylating agent decitabine anti-tumor therapy. Clin Cancer Res. 2017. https://doi.org/10.1158/1078-0432. CCR-17-1201.
127. Sigalotti L, Fratta E, Coral S, Maio M. Epigenetic drugs as immunomodulators for combination therapies in solid tumors. Pharmacol Ther. 2014; 142: 339-50. https://doi. org/10.1016/j.pharmthera.2013.12.015.
128. Terracina KP, Graham LJ, Payne KK, Manjili MH, Baek A, Damle SR, Bear HD. DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer. Cancer Immunol Immunother. 2016; 65: 1061-73. https://doi.org/10.1007/s00262-016-1868-8.
129. Bao L, Dunham K, Lucas K. MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells to facilitate cytotoxic T lymphocyte-mediated tumor cell killing. Cancer Immunol Immunother. 2011; 60: 1299-307. https://doi.org/10.1007/s00262-011-1037-z.
130. Xu P, Hu G, Luo C, Liang Z. DNA methyltransferase inhibitors: an updated patent review (2012-2015). Expert Opin Ther Pat. 2016; 26: 1017-30. https://doi.org/10.1080/ 13543776.2016.1209488.
131. Lucarini V, Buccione C, Ziccheddu G, Peschiaroli F, Sestili P, Puglisi R, Mattia G, Zanetti C, Parolini I, Bracci L, Macchia I, Rossi A, D'Urso MT, et al. Combining type I interferons and 5-aza-2'-deoxycitidine to improve antitumor response against melanoma. J Invest Dermatol. 2017; 137: 159-69. https://doi.org/10.1016/j.jid.2016.08.024.
132. Jazirehi AR, Nazarian R, Torres-Collado AX, Economou JS. Aberrant apoptotic machinery confers melanoma dual resistance to BRAF(V600E) inhibitor and immune effector cells: immunosensitization by a histone deacetylase inhibitor. Am J Clin Exp Immunol. 2014; 3: 43-56.
133. Yao Y, Zhou J, Wang L, Gao X, Ning Q, Jiang M, Wang J, Wang L, Yu L. Increased PRAME-specific CTL killing of acute myeloid leukemia cells by either a novel histone deacetylase inhibitor chidamide alone or combined treatment with decitabine. PLoS One. 2013; 8: e70522. https://doi.org/10.1371/journal.pone.0070522.
134. Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, Carter R, Awad W, Neale G, Thomas PG, Youngblood B. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell. 2017; 170: 142-57.e19. https://doi.org/10.1016/j.cell.2017.06.007.
135. Berger KN, Pu JJ. PD-1 pathway and its clinical application: a 20year journey after discovery of the complete human PD-1 gene. Gene. 2018; 638: 20-5. https://doi.org/10.1016/j. gene.2017.09.050.
136. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, Chaput N, Eggermont A, Marabelle A, Soria JC, Ferte C. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/ PD-L1. Clin Cancer Res. 2017; 23: 1920-8. https://doi. org/10.1158/1078-0432.ccr-16-1741.
137. Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017; 23: 4242-50. https:// doi.org/10.1158/1078-0432.ccr-16-3133.