REFERENCES
1. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, Adaptive, and acquired resistance to cancer immunotherapy. Cell 2017;168:707-23.
2. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 2018;8:1069-86.
4. Hoption Cann SA, van Netten JP, van Netten C. Dr William coley and tumour regression: a place in history or in the future. Postgrad Med J 2003;79:672-80.
6. Fares CM, Van Allen EM, Drake CG, Allison JP, Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book 2019;39:147-64.
7. De Sousa Linhares A, Leitner J, Grabmeier-Pfistershammer K, Steinberger P. Not all immune checkpoints are created equal. Front Immunol 2018;9:1909.
8. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature 1987;328:267-70.
9. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995;182:459-65.
10. 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;11:3887-95.
11. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, et al. 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 U S A 2002;99:12293-7.
12. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 2003;63:6501-5.
13. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 2005;65:1089-96.
14. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res 2011;17:6958-62.
15. Sambi M, Bagheri L, Szewczuk MR. Current challenges in cancer immunotherapy: multimodal approaches to improve efficacy and patient response rates. J Oncol 2019;2019:4508794.
16. Syn NL, Teng MWL, Mok TSK, Soo RA. De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol 2017;18:e731-41.
17. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 2018;118:9-16.
18. Gide TN, Wilmott JS, Scolyer RA, Long GV. Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma. Clin Cancer Res 2018;24:1260-70.
19. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 2014;515:577-81.
21. Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J 2018;24:47-53.
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. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 2013;31:e439-42.
24. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-13.
25. de Velasco G, Miao D, Voss MH, Hakimi AA, Hsieh JJ, et al. Tumor mutational load and immune parameters across metastatic renal cell carcinoma risk groups. Cancer Immunol Res 2016;4:820-2.
26. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015;5:43-51.
27. Neefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 2011;11:823-36.
28. 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.
29. Sucker A, Zhao F, Real B, Heeke C, Bielefeld N, et al. Genetic evolution of T-cell resistance in the course of melanoma progression. Clin Cancer Res 2014;20:6593-604.
30. 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.
31. Zhao F, Sucker A, Horn S, Heeke C, Bielefeld N, et al. Melanoma lesions independently acquire T-cell resistance during metastatic latency. Cancer Res 2016;76:4347-58.
32. 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.
33. Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun 2017;8:1136.
34. Pereira C, Gimenez-Xavier P, Pros E, Pajares MJ, Moro M, et al. Genomic profiling of patient-derived xenografts for lung cancer identifies B2M inactivation impairing immunorecognition. Clin Cancer Res 2017;23:3203-13.
35. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372:2509-20.
36. Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite Instability as a Biomarker for PD-1 Blockade. Clin Cancer Res 2016;22:813-20.
37. Karpf AR, Jones DA. Reactivating the expression of methylation silenced genes in human cancer. Oncogene 2002;21:5496-503.
38. 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.
39. Yoshihama S, Roszik J, Downs I, Meissner TB, Vijayan S, et al. NLRC5/MHC class I transactivator is a target for immune evasion in cancer. Proc Natl Acad Sci U S A 2016;113:5999-6004.
40. Burr ML, Sparbier CE, Chan KL, Chan YC, Kersbergen A, et al. An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer. Cancer Cell 2019;36:385-401.e8.
41. Dunn GP, Sheehan KC, Old LJ, Schreiber RD. IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. Cancer Res 2005;65:3447-53.
42. Heninger E, Krueger TE, Lang JM. Augmenting antitumor immune responses with epigenetic modifying agents. Front Immunol 2015;6:29.
43. Li X, Zhang Y, Chen M, Mei Q, Liu Y, et al. Increased IFNγ+ T cells are responsible for the clinical responses of low-dose DNA-demethylating agent decitabine antitumor therapy. Clin Cancer Res 2017;23:6031-43.
44. Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, et al. De Novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 2017;170:142-57.e19.
45. Terracina KP, Graham LJ, Payne KK, Manjili MH, Baek A, et al. DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer. Cancer Immunol Immunother 2016;65:1061-73.
46. Shen L, Ciesielski M, Ramakrishnan S, Miles KM, Ellis L, et al. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models. PLoS One 2012;7:e30815.
47. Orillion A, Hashimoto A, Damayanti N, Shen L, Adelaiye-Ogala R, et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res 2017;23:5187-201.
48. 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.
49. Agarwala SS, Moschos SJ, Johnson ML, Opyrchal M, Gabrilovich D, et al. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma progressing on or after a PD-1/L1 blocking antibody. J Clin Oncol 2018;36:9530.
50. Sullivan RJ, Moschos SJ, Johnson ML, Opyrchal M, Ordentlich P, et al. Abstract CT072: efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy. Cancer Res 2019;79:CT072.
51. Hellmann M, Jänne P, Opyrchal M, Hafez N, Raez L, et al. Efficacy/Safety of Entinostat (ENT) and Pembrolizumab (PEMBRO) in NSCLC patients previously treated with anti-PD-(L)1 therapy. J Thorac Oncol 2018;13:S330.
52. Gray JE, Saltos A, Tanvetyanon T, Haura EB, Creelan B, et al. Phase I/Ib study of pembrolizumab plus vorinostat in advanced/metastatic non-small cell lung cancer. Clin Cancer Res 2019;25:6623-32.
53. Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol 2020;20:25-39.
54. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015;523:231-5.
56. Zhao X, Subramanian S. Oncogenic pathways that affect antitumor immune response and immune checkpoint blockade therapy. Pharmacol Ther 2018;181:76-84.
57. Liu C, Peng W, Xu C, Lou Y, Zhang M, 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.
58. Chen N, Fang W, Zhan J, Hong S, Tang Y, et al. 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;10:910-23.
59. Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res 2015;21:4014-21.
60. Sumimoto H, Takano A, Teramoto K, Daigo Y. RAS-mitogen-activated protein kinase signal is required for enhanced PD-L1 expression in human lung cancers. PLoS One 2016;11:e0166626.
61. Donia M, Fagone P, Nicoletti F, Andersen RS, Hogdall E, et al. 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.
62. Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res 2016;22:1499-509.
63. Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin Cancer Res 2015;21:1639-51.
65. Peng W, McKenzie JA, Hwu P. Complementing T-cell function: an inhibitory role of the complement system in T-cell-mediated antitumor immunity. Cancer Discov 2016;6:953-5.
66. 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.
68. Luke JJ, Bao R, Sweis RF, Spranger S, Gajewski TF. WNT/beta-catenin pathway activation correlates with immune exclusion across human cancers. Clin Cancer Res 2019;25:3074-83.
69. Benci JL, Xu B, Qiu Y, Wu TJ, Dada H, et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 2016;167:1540-54.e12.
70. 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.
71. Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 2017;7:188-201.
72. Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 2014;41:830-42.
73. Corrales L, Gajewski TF. Molecular pathways: targeting the stimulator of interferon genes (STING) in the immunotherapy of cancer. Clin Cancer Res 2015;21:4774-9.
74. Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep 2015;11:1018-30.
75. Fu J, Kanne DB, Leong M, Glickman LH, McWhirter SM, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med 2015;7:283ra52.
76. Ager CR, Reilley MJ, Nicholas C, Bartkowiak T, Jaiswal AR, et al. Intratumoral STING activation with T-cell checkpoint modulation generates systemic antitumor immunity. Cancer Immunol Res 2017;5:676-84.
77. Rivera Vargas T, Benoit-Lizon I, Apetoh L. Rationale for stimulator of interferon genes-targeted cancer immunotherapy. Eur J Cancer 2017;75:86-97.
78. Ohkuri T, Ghosh A, Kosaka A, Zhu J, Ikeura M, et al. STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment. Cancer Immunol Res 2014;2:1199-208.
79. Koshy ST, Cheung AS, Gu L, Graveline AR, Mooney DJ. Liposomal delivery enhances immune activation by STING agonists for cancer immunotherapy. Adv Biosyst 2017;1:1600013.
80. Wilson DR, Sen R, Sunshine JC, Pardoll DM, Green JJ, et al. Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy. Nanomedicine 2018;14:237-46.
81. Challa SV, Zhou S, Sheri A, Padmanabhan S, Meher G, et al. Preclinical studies of SB 11285, a novel STING agonist for immuno-oncology. J Clin Oncol 2017;35:e14616.
82. Ricklefs FL, Alayo Q, Krenzlin H, Mahmoud AB, Speranza MC, et al. Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv 2018;4:eaar2766.
83. Theodoraki MN, Yerneni SS, Hoffmann TK, Gooding WE, Whiteside TL. Clinical significance of PD-L1(+) exosomes in plasma of head and neck cancer patients. Clin Cancer Res 2018;24:896-905.
84. Chen G, Huang AC, Zhang W, Zhang G, Wu M, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 2018;560:382-6.
85. Poggio M, Hu T, Pai CC, Chu B, Belair CD, et al. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell 2019;177:414-27.e13.
87. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133:775-87.
88. Liston A, Gray DH. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol 2014;14:154-65.
89. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005;201:723-35.
90. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000;192:303-10.
91. Cao X, Cai SF, Fehniger TA, Song J, Collins LI, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 2007;27:635-46.
92. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012;12:298-306.
93. Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 2011;9:204.
94. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 2013;210:1695-710.
95. Ha D, Tanaka A, Kibayashi T, Tanemura A, Sugiyama D, et al. Differential control of human Treg and effector T cells in tumor immunity by Fc-engineered anti-CTLA-4 antibody. Proc Natl Acad Sci U S A 2019;116:609-18.
96. Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 2018;33:649-63.e4.
97. Sharma N, Vacher J, Allison JP. TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion. Proc Natl Acad Sci U S A 2019;116:10453-62.
98. Heath DJ, Vanderkerken K, Cheng X, Gallagher O, Prideaux M, et al. An osteoprotegerin-like peptidomimetic inhibits osteoclastic bone resorption and osteolytic bone disease in myeloma. Cancer Res 2007;67:202-8.
99. Bronte V, Wang M, Overwijk WW, Surman DR, Pericle F, et al. Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. J Immunol 1998;161:5313-20.
100. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004;6:409-21.
101. 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.
102. de Coana YP, Wolodarski M, Poschke I, Yoshimoto Y, Yang Y, et al. Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget 2017;8:21539-53.
103. Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, et al. PI3Kgamma is a molecular switch that controls immune suppression. Nature 2016;539:437-42.
104. Foubert P, Kaneda MM, Varner JA. PI3Kgamma activates integrin alpha4 and promotes immune suppressive myeloid cell polarization during tumor progression. Cancer Immunol Res 2017;5:957-68.
105. Davis RJ, Moore EC, Clavijo PE, Friedman J, Cash H, et al. Anti-PD-L1 efficacy can be enhanced by inhibition of myeloid-derived suppressor cells with a selective inhibitor of PI3Kdelta/gamma. Cancer Res 2017;77:2607-19.
106. Wiezorek J, Holland P, Graves J. Death receptor agonists as a targeted therapy for cancer. Clin Cancer Res 2010;16:1701-8.
107. Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 2006;66:9299-307.
108. Adamson PC, Reaman G, Finklestein JZ, Feusner J, Berg SL, et al. Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer. J Clin Oncol 1997;15:3330-7.
109. Kusmartsev S, Cheng F, Yu B, Nefedova Y, Sotomayor E, et al. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res 2003;63:4441-9.
110. Tobin RP, Jordan KR, Robinson WA, Davis D, Borges VF, et al. Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab. Int Immunopharmacol 2018;63:282-91.
111. Karnes JH, Bastarache L, Shaffer CM, Gaudieri S, Xu Y, et al. Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants. Sci Transl Med 2017;9.
112. Scala S. Molecular pathways: targeting the CXCR4-CXCL12 axis--untapped potential in the tumor microenvironment. Clin Cancer Res 2015;21:4278-85.
113. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 2006;107:1761-7.
114. Hughes R, Qian BZ, Rowan C, Muthana M, Keklikoglou I, et al. Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res 2015;75:3479-91.
115. 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.
116. Mok S, Koya RC, Tsui C, Xu J, Robert L, et al. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res 2014;74:153-61.
117. Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017;545:495-9.
118. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. The Lancet Oncology 2016;17:e542-51.
119. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568-71.
120. Goff SL, Dudley ME, Citrin DE, Somerville RP, Wunderlich JR, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 2016;34:2389-97.
121. Wei F, Zhong S, Ma Z, Kong H, Medvec A, et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci U S A 2013;110:E2480-9.
122. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28.
123. Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 2015;14:847-56.
124. Blank CU, Haining WN, Held W, Hogan PG, Kallies A, et al. Defining ‘T cell exhaustion’. Nat Rev Immunol 2019;19:665-74.
125. Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, et al. Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol 2019;20:326-36.
126. Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 2019;50:195-211.e10.
127. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature 2019;571:211-8.
128. Ribas A, Shin DS, Zaretsky J, Frederiksen J, Cornish A, et al. PD-1 blockade expands intratumoral memory t cells. Cancer Immunol Res 2016;4:194-203.
129. Horn LA, Fousek K, Palena C. Tumor plasticity and resistance to immunotherapy. Trends Cancer 2020;6:432-41.
130. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015;527:525-30.
131. Fischer KR, Durrans A, Lee S, Sheng J, Li F, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015;527:472-6.
132. Byers LA, Diao L, Wang J, Saintigny P, Girard L, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 2013;19:279-90.
134. Cheng Y, Ma XL, Wei YQ, Wei XW. Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim Biophys Acta Rev Cancer 2019;1871:289-312.
135. Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, et al. An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell 2011;22:1686-98.
136. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018;554:544-8.
137. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018;554:538-43.
139. Pickup M, Novitskiy S, Moses HL. The roles of TGFbeta in the tumour microenvironment. Nat Rev Cancer 2013;13:788-99.
140. Dodagatta-Marri E, Meyer DS, Reeves MQ, Paniagua R, To MD, et al. α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas. J Immunother Cancer 2019;7:62.
141. Knudson KM, Hicks KC, Luo X, Chen JQ, Schlom J, et al. M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine. Oncoimmunology 2018;7:e1426519.
142. Lan Y, Zhang D, Xu C, Hance KW, Marelli B, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med 2018;10:eaan5488.
143. Strauss J, Heery CR, Schlom J, Madan RA, Cao L, et al. Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFβ, in advanced solid tumors. Clin Cancer Res 2018;24:1287-95.
144. Paolino M, Penninger JM. The role of TAM family receptors in immune cell function: implications for cancer therapy. Cancers (Basel) 2016;8.
145. Aguilera TA, Giaccia AJ. Molecular Pathways: Oncologic pathways and their role in T-cell exclusion and immune evasion-a new role for the AXL receptor tyrosine kinase. Clin Cancer Res 2017;23:2928-33.
146. Hamilton DH, Litzinger MT, Jales A, Huang B, Fernando RI, et al. Immunological targeting of tumor cells undergoing an epithelial-mesenchymal transition via a recombinant brachyury-yeast vaccine. Oncotarget 2013;4:1777-90.
147. Heery CR, Singh BH, Rauckhorst M, Marté JL, Donahue RN, et al. Phase I trial of a yeast-based therapeutic cancer vaccine (GI-6301) targeting the transcription factor brachyury. Cancer Immunol Res 2015;3:1248-56.
148. Heery CR, Palena C, McMahon S, Donahue RN, Lepone LM, et al. Phase I study of a poxviral TRICOM-based vaccine directed against the transcription factor brachyury. Clin Cancer Res 2017;23:6833-45.
149. Gatti-Mays ME, Redman JM, Donahue RN, Palena C, Madan RA, et al. A phase I trial using a multitargeted recombinant adenovirus 5 (CEA/MUC1/Brachyury)-based immunotherapy vaccine regimen in patients with advanced cancer. Oncologist 2019; doi: 10.1634/theoncologist.2019-0608.
151. Byrne KT, Vonderheide RH. CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer. Cell Rep 2016;15:2719-32.
152. Vonderheide RH, Flaherty KT, Khalil M, Stumacher MS, Bajor DL, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 2007;25:876-83.
153. Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol 2010;28:57-78.
154. Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res 2013;73:7189-98.
155. Sugamura K, Ishii N, Weinberg AD. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat Rev Immunol 2004;4:420-31.
156. Redmond WL, Linch SN, Kasiewicz MJ. Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immunol Res 2014;2:142-53.
157. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015;27:450-61.
158. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, 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;207:2175-86.
159. 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.
160. Granier C, Dariane C, Combe P, Verkarre V, Urien S, et al. Tim-3 expression on tumor-infiltrating PD-1(+)CD8(+) T cells correlates with poor clinical outcome in renal cell carcinoma. Cancer Res 2017;77:1075-82.
161. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014;26:923-37.
162. Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, et al. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 2015;125:4053-62.
163. Solomon BL, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother 2018;67:1659-67.
164. Liu W, Tang L, Zhang G, Wei H, Cui Y, et al. Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem 2004;279:18748-58.
165. Kouo T, Huang L, Pucsek AB, Cao M, Solt S, et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res 2015;3:412-23.
166. Jha V, Workman CJ, McGaha TL, Li L, Vas J, et al. Lymphocyte activation gene-3 (LAG-3) negatively regulates environmentally-induced autoimmunity. PLoS One 2014;9:e104484.
167. Ascierto PA, Bono P, Bhatia S, Melero I, Nyakas MS, et al. LBA18Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti-PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations. Ann Oncol 2017;28.
168. Chon SY, Hassanain HH, Gupta SL. Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene. J Biol Chem 1996;271:17247-52.
169. Yentz S, Smith D. Indoleamine 2,3-Dioxygenase (IDO) Inhibition as a strategy to augment cancer immunotherapy. BioDrugs 2018;32:311-7.
170. Smith C, Chang MY, Parker KH, Beury DW, DuHadaway JB, et al. IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov 2012;2:722-35.
171. Beatty GL, O’Dwyer PJ, Clark J, Shi JG, Bowman KJ, et al. First-in-Human Phase I study of the oral inhibitor of indoleamine 2,3-Dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res 2017;23:3269-76.
172. Mitchell TC, Hamid O, Smith DC, Bauer TM, Wasser JS, et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase i results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J Clin Oncol 2018; doi: 10.1200/JCO.2018.78.9602.
173. Long GV, Dummer R, Hamid O, Gajewski TF, Caglevic C, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol 2019;20:1083-97.
175. Motz GT, Santoro SP, Wang LP, Garrabrant T, Lastra RR, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 2014;20:607-15.
176. Chen PL, Roh W, Reuben A, Cooper ZA, Spencer CN, et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov 2016;6:827-37.
177. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 2015;212:139-48.
178. Ohm JE, Gabrilovich DI, Sempowski GD, Kisseleva E, Parman KS, et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 2003;101:4878-86.
179. Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 2013;73:539-49.
180. Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol 2013;172:500-6.
181. Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 2016;7:12624.
182. Bergerot P, Lamb P, Wang E, Pal SK. Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence. Mol Cancer Ther 2019;18:2185-93.
183. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116-27.
184. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103-15.
185. Hsu C-H, Lee MS, Lee KH, Numata K, Stein S, et al. LBA7Randomised efficacy and safety results for atezolizumab (Atezo) + bevacizumab (Bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC). Ann Oncol 2019;30.
186. Lane ER, Zisman TL, Suskind DL. The microbiota in inflammatory bowel disease: current and therapeutic insights. J Inflamm Res 2017;10:63-73.
187. Zitvogel L, Daillere R, Roberti MP, Routy B, Kroemer G. Anticancer effects of the microbiome and its products. Nat Rev Microbiol 2017;15:465-78.
188. Zitvogel L, Ayyoub M, Routy B, Kroemer G. Microbiome and anticancer immunosurveillance. Cell 2016;165:276-87.
189. Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J Immunother Cancer 2019;7:108.
190. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97-103.
191. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359:104-8.
192. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91-7.
193. Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015;350:1079-84.
194. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol 2018;29:1437-44.
195. Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 2019;5:1774-8.
196. Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, et al. Commensal bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350:1084-9.
197. Baruch EN, Youngster I, Ortenberg R, Ben-Betzalel G, Katz LH, et al. Abstract CT042: fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 therapy in refractory metastatic melanoma patients - preliminary results from a phase I clinical trial (NCT03353402). Cancer Res 2019;79:CT042-CT.
198. Butterfield LH, Disis ML, Fox BA, Kaufman DR, Khleif SN, et al. SITC 2018 workshop report: immuno-oncology biomarkers: state of the art. J Immunother Cancer 2018;6:138.
199. Balli D, Rech AJ, Stanger BZ, Vonderheide RH. Immune cytolytic activity stratifies molecular subsets of human pancreatic cancer. Clin Cancer Res 2017;23:3129-38.
200. Blando J, Sharma A, Higa MG, Zhao H, Vence L, et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc Natl Acad Sci U S A 2019;116:1692-7.
201. Lee JJ, Powderly JD, Patel MR, Brody J, Hamilton EP, et al. Phase 1 trial of CA-170, a novel oral small molecule dual inhibitor of immune checkpoints PD-1 and VISTA, in patients (pts) with advanced solid tumor or lymphomas. J Clin Oncol 2017;35:TPS3099.
202. Tolcher AW, Sznol M, Hu-Lieskovan S, Papadopoulos KP, Patnaik A, et al. Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res 2017;23:5349-57.
203. Soldevilla MM, Villanueva H, Meraviglia-Crivelli D, Menon AP, Ruiz M, et al. ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity. Mol Ther 2019;27:1878-91.
204. Zappasodi R, Sirard C, Li Y, Budhu S, Abu-Akeel M, et al. Rational design of anti-GITR-based combination immunotherapy. Nat Med 2019;25:759-66.
205. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005;11:6713-21.
206. Germano G, Lamba S, Rospo G, Barault L, Magrì A, et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 2017;552:116-20.
207. Wakita D, Iwai T, Harada S, Suzuki M, Yamamoto K, et al. Cisplatin augments antitumor T-cell responses leading to a potent therapeutic effect in combination with PD-L1 blockade. Anticancer Res 2019;39:1749-60.
208. Zhu L, Chen L. Progress in research on paclitaxel and tumor immunotherapy. Cell Mol Biol Lett 2019;24:40.
209. Ganesh S, Shui X, Craig KP, Park J, Wang W, et al. RNAi-mediated β-catenin inhibition promotes T cell infiltration and antitumor activity in combination with immune checkpoint blockade. Mol Ther 2018;26:2567-79.
210. Kawazoe A, Kuboki Y, Komatsu Y, Nishina T, Shinozaki E, et al. Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503. J Clin Oncol 2018;36:760.
211. Luo N, Formisano L, Gonzalez-Ericsson PI, Sanchez V, Dean PT, et al. Melanoma response to anti-PD-L1 immunotherapy requires JAK1 signaling, but not JAK2. Oncoimmunology 2018;7:e1438106.
212. 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.
213. Jiang P, Gu S, Pan D, Fu J, Sahu A, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 2018;24:1550-8.
214. Beavis PA, Milenkovski N, Henderson MA, John LB, Allard B, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res 2015;3:506-17.
215. Chen L, Diao L, Yang Y, Yi X, Rodriguez BL, et al. CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade. Cancer Discov 2018;8:1156-75.
216. Maj T, Wang W, Crespo J, Zhang H, Wang W, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 2017;18:1332-41.
217. Perrot I, Michaud HA, Giraudon-Paoli M, Augier S, Docquier A, et al. Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies. Cell Rep 2019;27:2411-25.e9.
218. Iannone R, Miele L, Maiolino P, Pinto A, Morello S. Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am J Cancer Res 2014;4:172-81.
219. Leone RD, Sun IM, Oh MH, Sun IH, Wen J, et al. Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models. Cancer Immunol Immunother 2018;67:1271-84.
220. Doi T, Muro K, Ishii H, Kato T, Tsushima T, et al. A phase I study of the anti-CC chemokine receptor 4 antibody, mogamulizumab, in combination with nivolumab in patients with advanced or metastatic solid tumors. Clin Cancer Res 2019;25:6614-22.
221. Buchbinder EI, Dutcher JP, Daniels GA, Curti BD, Patel SP, et al. Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition. J Immunother Cancer 2019;7:49.
222. Puca E, Probst P, Stringhini M, Murer P, Pellegrini G, et al. The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8(+) T cell activity and synergizes with immune checkpoint inhibitors. Int J Cancer 2020;146:2518-30.
223. Berraondo P, Etxeberria I, Ponz-Sarvise M, Melero I. Revisiting interleukin-12 as a cancer immunotherapy agent. Clin Cancer Res 2018;24:2716-8.
224. Zhao M, Luo M, Xie Y, Jiang H, Cagliero C, et al. Development of a recombinant human IL-15·sIL-15Rα/Fc superagonist with improved half-life and its antitumor activity alone or in combination with PD-1 blockade in mouse model. Biomed Pharmacother 2019;112:108677.
225. Jung H, Bischof A, Ebsworth K, Ertl L, Schall T, et al. Combination therapy of chemokine receptor inhibition plus PDL-1 blockade potentiates anti-tumor effects in a murine model of breast cancer. J Immunother Cancer 2015;3:P227.
226. Flores-Toro JA, Luo D, Gopinath A, Sarkisian MR, Campbell JJ, et al. CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas. Proc Natl Acad Sci U S A 2020;117:1129-38.
227. Jung H, Ertl L, Janson C, Schall T, Charo I. Abstract A107: Inhibition of CCR2 potentiates the checkpoint inhibitor immunotherapy in pancreatic cancer. Cancer Immunol Res 2016;4:A107.
228. Dominguez C, McCampbell KK, David JM, Palena C. Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer. JCI insight 2017;2:e94296.
229. Greene S, Robbins Y, Mydlarz WK, Huynh AP, Schmitt NC, et al. Inhibition of MDSC trafficking with SX-682, a CXCR1/2 inhibitor, enhances NK-Cell immunotherapy in head and neck cancer models. Clin Cancer Res 2020;26:1420-31.
230. Steele CW, Karim SA, Leach JDG, Bailey P, Upstill-Goddard R, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 2016;29:832-45.
231. Mullinax JE, Hall M, Prabhakaran S, Weber J, Khushalani N, et al. Combination of ipilimumab and adoptive cell therapy with tumor-infiltrating lymphocytes for patients with metastatic melanoma. Front Oncol 2018;8:44.
232. Zhang R, Deng Q, Jiang YY, Zhu HB, Wang J, et al. Effect and changes in PD-1 expression of CD19 CAR-T cells from T cells highly expressing PD-1 combined with reduced-dose PD-1 inhibitor. Oncol Rep 2019;41:3455-63.
233. Peng M, Mo Y, Wang Y, Wu P, Zhang Y, et al. Neoantigen vaccine: an emerging tumor immunotherapy. Molecular Cancer 2019;18.
234. Wang T, Zheng N, Luo Q, Jiang L, He B, et al. Probiotics lactobacillus reuteri abrogates immune checkpoint blockade-associated colitis by inhibiting group 3 innate lymphoid cells. Front Immunol 2019;10:1235.
235. 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.
236. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015;520:373-7.
237. Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol 2015;1:1325-32.
238. Lemdani K, Mignet N, Boudy V, Seguin J, Oujagir E, et al. Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma. Oncoimmunology 2019;8:1550342.
239. Aarts BM, Klompenhouwer EG, Rice SL, Imani F, Baetens T, et al. Cryoablation and immunotherapy: an overview of evidence on its synergy. Insights into Imaging 2019;10.
240. Ray A, Williams MA, Meek SM, Bowen RC, Grossmann KF, et al. A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma. Oncotarget 2016;7:64390-9.
241. Weide B, Derhovanessian E, Pflugfelder A, Eigentler TK, Radny P, et al. High response rate after intratumoral treatment with interleukin-2: results from a phase 2 study in 51 patients with metastasized melanoma. Cancer 2010;116:4139-46.
242. Langan EA, Kümpers C, Graetz V, Perner S, Zillikens D, et al. Intralesional interleukin-2: a novel option to maximize response to systemic immune checkpoint therapy in loco-regional metastatic melanoma. Dermatol Ther 2019;32:e12901.
243. Rafei-Shamsabadi D, Lehr S, von Bubnoff D, Meiss F. Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone. Cancer Immunol Immunother 2019;68:1417-28.
244. Chowdhury S, Castro S, Coker C, Hinchliffe TE, Arpaia N, et al. Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat Med 2019;25:1057-63.
245. Marabelle A, Tselikas L, De Baere T, Houot R. Intratumoral immunotherapy: using the tumor as the remedy. Ann Oncol 2017;28:xii33-43.
