REFERENCES
2. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48.
3. Delahunt B, Srigley JR, Egevad L, Montironi R. International society of urological pathology grading and other prognostic factors for renal neoplasia. Eur Urol 2014;66:795-8.
4. Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med 2017;376:354-66.
5. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-90.
6. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010;116:4256-65.
7. Itsumi M, Tatsugami K. Immunotherapy for renal cell carcinoma. Clin Dev Immunol 2010;2010:284581.
8. Roy AM, Briggler A, Tippit D, Dawson K, Verma R. Neoadjuvant cabozantinib in renal-cell carcinoma: a brief review. Clin Genitourin Cancer 2020;18:e688-91.
9. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-13.
10. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277-90.
11. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open 2020;5:e001079.
12. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116-27.
13. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103-15.
14. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol 2022;23:888-98.
15. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021;384:1289-300.
16. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1-10.
17. Keir ME, Liang SC, Guleria I, et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 2006;203:883-95.
18. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677-704.
19. 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.
20. Ross K, Jones RJ. Immune checkpoint inhibitors in renal cell carcinoma. Clin Sci 2017;131:2627-42.
21. 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.
22. Rizvi H, Sanchez-Vega F, La K, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 2018;36:633-41.
23. Ladoire S, Arnould L, Apetoh L, et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells. Clin Cancer Res 2008;14:2413-20.
24. Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines 2016;4:28.
26. Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol 2012;3:51.
27. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004;10:942-9.
28. Tang Y, Xu X, Guo S, et al. An increased abundance of tumor-infiltrating regulatory T cells is correlated with the progression and prognosis of pancreatic ductal adenocarcinoma. PLoS One 2014;9:e91551.
29. Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 2015;5:15179.
30. Griffiths RW, Elkord E, Gilham DE, et al. Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother 2007;56:1743-53.
31. Rodríguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 2008;222:180-91.
32. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 2004;172:989-99.
33. Ochoa AC, Zea AH, Hernandez C, Rodriguez PC. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res 2007;13:721s-6s.
34. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23:549-55.
35. Hao NB, Lü MH, Fan YH, Cao YL, Zhang ZR, Yang SM. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol 2012;2012:948098.
36. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 2014;6:1670-90.
37. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4:71-8.
38. Van Ginderachter JA, Movahedi K, Hassanzadeh Ghassabeh G, et al. Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology 2006;211:487-501.
39. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity 2014;41:49-61.
40. Tsutsui S, Yasuda K, Suzuki K, Tahara K, Higashi H, Era S. Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep 2005;14:425-31.
41. Zijlmans HJ, Fleuren GJ, Baelde HJ, Eilers PH, Kenter GG, Gorter A. The absence of CCL2 expression in cervical carcinoma is associated with increased survival and loss of heterozygosity at 17q11.2. J Pathol 2006;208:507-17.
42. Gil M, Komorowski MP, Seshadri M, et al. CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells. J Immunol 2014;193:5327-37.
43. Rabin RL, Park MK, Liao F, Swofford R, Stephany D, Farber JM. Chemokine receptor responses on T cells are achieved through regulation of both receptor expression and signaling. J Immunol 1999;162:3840-50.
44. Najafi M, Farhood B, Mortezaee K. Contribution of regulatory T cells to cancer: a review. J Cell Physiol 2019;234:7983-93.
45. Motz GT, Santoro SP, Wang LP, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 2014;20:607-15.
46. Braun DA, Street K, Burke KP, et al. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell 2021;39:632-48.e8.
47. Zhang L, Yu X, Zheng L, et al. Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature 2018;564:268-72.
48. Becht E, Giraldo NA, Lacroix L, et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol 2016;17:218.
49. Giraldo NA, Becht E, Pagès F, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res 2015;21:3031-40.
50. Motzer RJ, Robbins PB, Powles T, et al. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN renal 101 trial. Nat Med 2020;26:1733-41.
51. Voss MH, Buros Novik J, Hellmann MD, et al. Correlation of degree of tumor immune infiltration and insertion-and-deletion (indel) burden with outcome on programmed death 1 (PD1) therapy in advanced renal cell cancer (RCC). J Clin Oncol 2018;36:4518.
52. 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.
53. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016;375:819-29.
54. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol 1997;15:749-95.
55. Garcia-Diaz A, Shin DS, Moreno BH, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep 2017;19:1189-201.
56. Goodman AM, Piccioni D, Kato S, et al. Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors. JAMA Oncol 2018;4:1237-44.
57. Shin DS, Zaretsky JM, Escuin-Ordinas H, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 2017;7:188-201.
58. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007;26:3279-90.
59. Loi S, Dushyanthen S, Beavis PA, 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.
61. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015;523:231-5.
62. Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov 2016;6:202-16.
63. Cai C, Xu YF, Wu ZJ, et al. Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma. World J Urol 2016;34:561-7.
64. Thommen DS, Schreiner J, Müller P, 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.
65. Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 2016;7:10501.
66. Shayan G, Srivastava R, Li J, Schmitt N, Kane LP, Ferris RL. Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer. Oncoimmunology 2017;6:e1261779.
67. Ngiow SF, Young A, Jacquelot N, et al. A threshold level of intratumor CD8+ T-cell PD1 expression dictates therapeutic response to Anti-PD1. Cancer Res 2015;75:3800-11.
68. Oyewole-Said D, Konduri V, Vazquez-Perez J, Weldon SA, Levitt JM, Decker WK. Beyond T-cells: functional characterization of CTLA-4 expression in immune and non-immune cell types. Front Immunol 2020;11:608024.
69. Ribas A, Shin DS, Zaretsky J, et al. PD-1 blockade expands intratumoral memory T cells. Cancer Immunol Res 2016;4:194-203.
70. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer 2018;118:9-16.
71. Sormendi S, Wielockx B. Hypoxia pathway proteins as central mediators of metabolism in the tumor cells and their microenvironment. Front Immunol 2018;9:40.
72. Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 2018;15:310-24.
73. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97-103.
74. Lalani AA, Xie W, Braun DA, et al. Effect of antibiotic use on outcomes with systemic therapies in metastatic renal cell carcinoma. Eur Urol Oncol 2020;3:372-81.
75. Derosa L, Hellmann MD, Spaziano 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.
76. Tinsley N, Zhou C, Tan G, et al. Cumulative antibiotic use significantly decreases efficacy of checkpoint inhibitors in patients with advanced cancer. Oncologist 2020;25:55-63.
77. Bucsek MJ, Qiao G, MacDonald CR, et al. β-adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy. Cancer Res 2017;77:5639-51.
78. Mori K, Quhal F, Yanagisawa T, et al. The effect of immune checkpoint inhibitor combination therapies in metastatic renal cell carcinoma patients with and without previous cytoreductive nephrectomy: a systematic review and meta-analysis. Int Immunopharmacol 2022;108:108720.
79. Rassy E, Dalban C, Colomba E, et al. Efficacy and safety of concomitant proton pump inhibitor and nivolumab in renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase II study. Clin Genitourin Cancer 2022;20:488-94.
80. Wolchok JD, Saenger Y. The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist 2008;13 Suppl 4:2-9.
81. Zaremba A, Eggermont AMM, Robert C, et al. The concepts of rechallenge and retreatment with immune checkpoint blockade in melanoma patients. Eur J Cancer 2021;155:268-80.
82. Atkins MB, Jegede OA, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naive patients with advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A). J Clin Oncol 2022;40:2913-23.
83. Grimm MO, Esteban E, Barthélémy P, et al. Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC). J Clin Oncol 2021;39:4576.
84. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet 2023;402:185-95.
85. Choueiri TK, Albiges L, Hammers HJ, et al. TiNivo-2: a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor. J Clin Oncol 2022;40:TPS405.
86. Roy AM, George S. Management of immune-mediated toxicities and their implications in the outcomes of advanced kidney cancer. Immunotherapy 2023;15:397-400.
87. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol 2023;41:603.
88. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018;15:325-40.
89. Alfaro C, Suarez N, Gonzalez A, et al. Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes. Br J Cancer 2009;100:1111-9.
90. Huang Y, Chen X, Dikov MM, et al. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood 2007;110:624-31.
91. Adotevi O, Pere H, Ravel P, et al. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 2010;33:991-8.
92. Ohm JE, Gabrilovich DI, Sempowski GD, et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 2003;101:4878-86.
93. Rassy E, Flippot R, Albiges L. Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma. Ther Adv Med Oncol 2020;12:1758835920907504.
94. Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 2016;7:12624.
95. Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015;527:249-53.
96. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018;554:544-8.
97. Granier C, Dariane C, Combe P, 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.
98. Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res 2009;15:6225-31.
99. Guo ZS, Liu Z, Bartlett DL. Oncolytic immunotherapy: dying the right way is a key to eliciting potent antitumor immunity. Front Oncol 2014;4:74.
100. Gibney GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res 2015;21:712-20.
101. Kim S, Ha HK, Lim S, et al. Phase II trial of pexa-vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, in patients with metastatic, refractory renal cell carcinoma (RCC). J Clin Oncol 2018;36:671.