REFERENCES
1. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.
2. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26.
3. Robert C, Schachter J, Long GV, Arance A, Grob JJ, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015;372:2521-32.
4. Robert C, Long GV, Brady B, Dutriaux C, Maio M, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320-30.
5. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39.
6. Powles T, Duran I, van der Heijden MS, Loriot Y, Vogelzang NJ, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018;391:748-57.
7. Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2015;33:2004-12.
8. Schachter J, Ribas A, Long GV, Arance A, Grob JJ, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 2017;390:1853-62.
9. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23-34.
10. Miller J, Baker C, Cook K, Graf B, Sanchez-Lockhart M, et al. Two pathways of costimulation through CD28. Immunol Res 2009;45:159-72.
11. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405-13.
12. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25:9543-53.
13. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011;332:600-3.
14. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322:271-5.
15. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009;114:1537-44.
16. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793-800.
17. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 2012;209:1201-17.
18. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009;206:3015-29.
20. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014;505:495-501.
21. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, et al. Signatures of mutational processes in human cancer. Nature 2013;500:415-21.
22. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-8.
23. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189-99.
24. Royal RE, Levy C, Turner K, Mathur A, Hughes M, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33:828-33.
25. Deng L, Liang H, Burnette B, Beckett M, Darga T, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014;124:687-95.
26. Menard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 2008;57:1579-87.
27. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell 2017;170:1109-19 e10.
28. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-92.
29. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463-9.
30. Day RS. Treatment sequencing, asymmetry, and uncertainty: protocol strategies for combination chemotherapy. Cancer Res 1986;46:3876-85.
31. Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell 2017;168:542.
32. Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, et al. A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell 2018;175:984-97.e24.
33. Schaer DA, Beckmann RP, Dempsey JA, Huber L, Forest A, et al. The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade. Cell Rep 2018;22:2978-94.
34. del Campo AB, Kyte JA, Carretero J, Zinchencko S, Mendez R, et al. Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. Int J Cancer 2014;134:102-13.
35. Anagnostou V, Smith KN, Forde PM, Niknafs N, Bhattacharya R, et al. Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non-Small Cell Lung Cancer. Cancer Discov 2017;7:264-76.
36. Mulligan JK, Day TA, Gillespie MB, Rosenzweig SA, Young MR. Secretion of vascular endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions. Hum Immunol 2009;70:375-82.
37. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998;160:1224-32.
38. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 2010;70:6171-80.
39. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res 2014;2:632-42.
40. Peng W, Chen JQ, Liu C, Malu S, Creasy C, et al. Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer Discov 2016;6:202-16.
41. George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ, et al. Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma. Immunity 2017;46:197-204.
42. Holtzhausen A, Zhao F, Evans KS, Tsutsui M, Orabona C, et al. Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy. Cancer Immunol Res 2015;3:1082-95.
43. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 2015;523:231-5.
44. Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov 2018;8:822-35.
45. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med 2016;375:819-29.
46. Gao J, Shi LZ, Zhao H, Chen J, Xiong L, 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.
47. Sigalotti L, Fratta E, Coral S, Maio M. Epigenetic drugs as immunomodulators for combination therapies in solid tumors. Pharmacol Ther 2014;142:339-50.
48. Coral S, Sigalotti L, Altomonte M, Engelsberg A, Colizzi F, et al. 5-aza-2’-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: immunotherapeutic implications. Clin Cancer Res 2002;8:2690-5.
49. Fonsatti E, Nicolay HJ, Sigalotti L, Calabro L, Pezzani L, et al. Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2’-deoxycytidine in cutaneous melanoma: immunotherapeutic implications. Clin Cancer Res 2007;13:3333-8.
50. Woods DM, Woan K, Cheng F, Wang H, Perez-Villarroel P, et al. The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity. Melanoma Res 2013;23:341-8.
51. Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015;527:249-53.
52. Aspeslagh S, Morel D, Soria JC, Postel-Vinay S. Epigenetic modifiers as new immunomodulatory therapies in solid tumours. Ann Oncol 2018;29:812-24.
53. Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, et al. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study. Cancer Discov 2018; doi: 10.1158/2159-8290.CD-18-0774.
54. Zhu C, Anderson AC, Kuchroo VK. TIM-3 and its regulatory role in immune responses. Curr Top Microbiol Immunol 2011;350:1-15.
55. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 2007;27:670-84.
56. Thommen DS, Schreiner J, Muller P, Herzig P, Roller A, 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.
57. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 2016;7:10501.
58. Kim JE, Patel MA, Mangraviti A, Kim ES, Theodros D, et al. Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas. Clinical Cancer Research 2017;23:124-36.
59. Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, et al. TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J Clin Invest 2015;125:2046-58.
60. Kuklinski LF, Yan S, Li Z, Fisher JL, Cheng C, et al. VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Cancer Immunol Immunother 2018;67:1113-21.
61. 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.
62. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009;10:29-37.
63. 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;77:4911-27.
64. Daud AI, Loo K, Pauli ML, Sanchez-Rodriguez R, Sandoval PM, et al. Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma. J Clin Invest 2016;126:3447-52.
65. Schietinger A, Philip M, Krisnawan VE, Chiu EY, Delrow JJ, et al. Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis. Immunity 2016;45:389-401.
66. Philip M, Fairchild L, Sun L, Horste EL, Camara S, et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 2017;545:452-6.
67. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012;12:253-68.
68. Sade-Feldman M, Kanterman J, Klieger Y, Ish-Shalom E, Olga M, et al. Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab. Clin Cancer Res 2016;22:5661-72.
69. Gebhardt C, Sevko A, Jiang H, Lichtenberger R, Reith M, et al. Myeloid Cells and Related Chronic Inflammatory Factors as Novel Predictive Markers in Melanoma Treatment with Ipilimumab. Clin Cancer Res 2015;21:5453-9.
70. Weber J, Gibney G, Kudchadkar R, Yu B, Cheng P, et al. Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab. Cancer Immunol Res 2016;4:345-53.
71. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, et al. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med 2014;6:237ra67.
72. De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature 2016;539:443-7.
73. Christmas BJ, Rafie CI, Hopkins AC, Scott BA, Ma HS, et al. Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs. Cancer Immunol Res 2018;6:1561-77.
74. Ornstein MC, Diaz-Montero CM, Rayman P, Elson P, Haywood S, et al. Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy. Urol Oncol 2018;36:405-12.
75. Steidl C, Lee T, Shah SP, Farinha P, Han G, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med 2010;362:875-85.
76. Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, et al. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 2011;167:e211-9.
77. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011;1:54-67.
78. Strachan DC, Ruffell B, Oei Y, Bissell MJ, Coussens LM, et al. CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8(+) T cells. Oncoimmunology 2013;2:e26968.
79. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 2014;25:846-59.
80. Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, et al. 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.
81. van Baren N, Van den Eynde BJ. Tryptophan-degrading enzymes in tumoral immune resistance. Front Immunol 2015;6:34.
82. Hwu P, Du MX, Lapointe R, Do M, Taylor MW, et al. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol 2000;164:3596-9.
83. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003;9:1269-74.
84. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, et al. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 2002;196:459-68.
85. 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.
86. Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res 2014;20:5290-301.
87. Long GV, Dummer R, Hamid O, Gajewski T, Caglevic C, et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study. J Clin Oncol 2018;36:108.
88. Gibney GT, Hamid O, Gangadhar TC, Lutzky J, Olszanski AJ, et al. Preliminary results from a phase 1/2 study of INCB024360 combined with ipilimumab (ipi) in patients (pts) with melanoma. J Clin Oncol 2014;32:3010.
89. Jin D, Fan J, Wang L, Thompson LF, Liu A, et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res 2010;70:2245-55.
90. Allard B, Pommey S, Smyth MJ, Stagg J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res 2013;19:5626-35.
92. Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 2005;8:369-80.
93. Hanks BA, Holtzhausen A, Evans K, Heid M, Blobe GC. Combinatorial TGF-β signaling blockade and anti-CTLA-4 antibody immunotherapy in a murine BRAFV600E-PTEN-/- transgenic model of melanoma. J Clin Oncol 2014;32:3011.
94. de Gramont A, Faivre S, Raymond E. Novel TGF-beta inhibitors ready for prime time in onco-immunology. Oncoimmunology 2017;6:e1257453.
95. La Shu S, Yang Y, Allen CL, Maguire O, Minderman H, et al. Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment. Sci Rep 2018;8:12905.
96. Tuccitto A, Tazzari M, Beretta V, Rini F, Miranda C, et al. Immunomodulatory factors control the fate of melanoma tumor initiating cells. Stem Cells 2016;34:2449-60.
97. Hugo W, Shi H, Sun L, Piva M, Song C, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 2015;162:1271-85.
98. Ackerman A, Klein O, McDermott DF, Wang W, Ibrahim N, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014;120:1695-701.
