REFERENCES
2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.
3. Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer 2018;103:356-87.
4. Capitanio U, Bensalah K, Bex A, et al. Epidemiology of renal cell carcinoma. Eur Urol 2019;75:74-84.
5. Dabestani S, Thorstenson A, Lindblad P, Harmenberg U, Ljungberg B, Lundstam S. Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study. World J Urol 2016;34:1081-6.
6. Rosenblatt J, McDermott DF. Immunotherapy for renal cell carcinoma. Hematol Oncol Clin North Am 2011;25:793-812.
7. Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med 2017;376:354-66.
8. Clark JI, Wong MKK, Kaufman HL, et al. Impact of sequencing targeted therapies with high-dose interleukin-2 immunotherapy: an analysis of outcome and survival of patients with metastatic renal cell carcinoma from an on-going observational IL-2 clinical trial: PROCLAIMSM. Clin Genitourin Cancer 2017;15:31-41.e4.
9. Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. J Clin Oncol 2013;31:3791-9.
10. Motzer RJ, Powles T, Atkins MB, et al. Final overall survival and molecular analysis in immotion151, a phase 3 trial comparing atezolizumab plus bevacizumab
11. Navani V, Heng DYC. Treatment selection in first-line metastatic renal cell carcinoma-the contemporary treatment paradigm in the age of combination therapy: a review. JAMA Oncol 2022;8:292-9.
12. Kluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer 2020;8:e000398.
13. Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1-update and clarification: from the recist committee. Eur J Cancer 2016;62:132-7.
14. Navani V, Graves MC, Mandaliya H, et al. Melanoma: an immunotherapy journey from bench to bedside. Cancer Treat Res 2022;183:49-89.
15. Conforti F, Pala L, Bagnardi V, et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol 2018;19:737-46.
16. Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res 2006;84:370-8.
17. Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol 2007;19:337-43.
18. Motzer RJ, Tykodi SS, Escudier B, et al. Final analysis of the CheckMate 025 trial comparing nivolumab (NIVO) versus everolimus (EVE) with > 5 years of follow-up in patients with advanced renal cell carcinoma (aRCC). J Clin Oncol 2020;38:617-617.
19. Farag KI, Makkouk A, Norian LA. Re-evaluating the effects of obesity on cancer immunotherapy outcomes in renal cancer: what do we really know? Front Immunol 2021;12:668494.
20. Sanchez A, Furberg H, Kuo F, et al. Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study. Lancet Oncol 2020;21:283-93.
21. Labadie BW, Liu P, Bao R, et al. BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma. J Transl Med 2019;17:386.
22. Bergerot PG, Bergerot CD, Philip EJ, et al. Targeted therapy and immunotherapy: effect of body mass index on clinical outcomes in patients diagnosed with metastatic renal cell carcinoma. Kidney Cancer 2019;3(1):63-70.
23. De Giorgi U, Procopio G, Giannarelli D, et al. Association of systemic inflammation index and body mass index with survival in patients with renal cell cancer treated with nivolumab. Clin Cancer Res 2019;25:3839-46.
24. Boi SK, Orlandella RM, Gibson JT, et al. Obesity diminishes response to PD-1-based immunotherapies in renal cancer. J Immunother Cancer 2020;8:e000725.
25. Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 2018;359:582-7.
26. Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nat Med 2019;25:1715-20.
27. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91-7.
28. Dizman N, Hsu J, Bergerot PG, et al. Randomized trial assessing impact of probiotic supplementation on gut microbiome and clinical outcome from targeted therapy in metastatic renal cell carcinoma. Cancer Med 2021;10:79-86.
29. Elkrief A, Derosa L, Kroemer G, Zitvogel L, Routy B. The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? Ann Oncol 2019;30:1572-9.
30. 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.
31. 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.
32. 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.
33. Arbour KC, Mezquita L, Long N, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2018;36:2872-8.
34. Santini FC, Rizvi H, Plodkowski AJ, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res 2018;6:1093-9.
35. Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at memorial sloan kettering cancer center. J Clin Oncol 2015;33:3193-8.
36. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 2017;35:785-92.
37. Watson AS, Goutam S, Stukalin I, et al. Association of immune-related adverse events, hospitalization, and therapy resumption with survival among patients with metastatic melanoma receiving single-agent or combination immunotherapy. JAMA Netw Open 2022;5:e2245596.
38. Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol 2020;20:25-39.
39. Restifo NP, Esquivel F, Kawakami Y, et al. Identification of human cancers deficient in antigen processing. J Exp Med 1993;177:265-72.
40. Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 2005;5:375-86.
41. 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.
42. Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res 2010;70:5213-9.
43. Ricketts CJ, De Cubas AA, Fan H, et al. Cancer genome atlas research network. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep 2018;23:313-326.e5.
44. Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov 2016;6:202-16.
45. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015;523:231-5.
46. Sweis RF, Spranger S, Bao R, et al. Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol Res 2016;4:563-8.
47. Seiwert TY, Zuo Z, Keck MK, et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res 2015;21:632-41.
48. Jiménez-Sánchez A, Memon D, Pourpe S, et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 2017;170:927-938.e20.
49. Sarvaria A, Madrigal JA, Saudemont A. B cell regulation in cancer and anti-tumor immunity. Cell Mol Immunol 2017;14:662-74.
50. Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity 2015;42:607-12.
52. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 2014;6:1670-90.
53. Komohara Y, Hasita H, Ohnishi K, et al. Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci 2011;102:1424-31.
54. Santoni M, Massari F, Amantini C, et al. Emerging role of tumor-associated macrophages as therapeutic targets in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother 2013;62:1757-68.
55. 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;36:4518-4518.
56. Vano Y, Rioux-leclercq N, Dalban C, et al. NIVOREN GETUG-AFU 26 translational study: association of PD-1, AXL, and PBRM-1 with outcomes in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) treated with nivolumab (N). J Clin Oncol 2020;38:618-618.
57. Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012;12:298-306.
58. 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.
59. Choueiri TK, Escudier B, Powles T, et al. METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917-27.
60. Zhang S, Zhang E, Long J, et al. Immune infiltration in renal cell carcinoma. Cancer Sci 2019;110:1564-72.
61. Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 2020;577:549-55.
62. Finkin S, Yuan D, Stein I, et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol 2015;16:1235-44.
63. Stubbs M, McSheehy PM, Griffiths JR, Bashford CL. Causes and consequences of tumour acidity and implications for treatment. Mol Med Today 2000;6:15-9.
64. Sormendi S, Wielockx B. Hypoxia pathway proteins as central mediators of metabolism in the tumor cells and their microenvironment. Front Immunol 2018;9:40.
65. Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 2018;15:310-24.
66. Garcia-Lora A, Algarra I, Garrido F. MHC class I antigens, immune surveillance, and tumor immune escape. J Cell Physiol 2003;195:346-55.
67. Yu W, Guo Y. Prognostic significance of programmed death ligand-1 immunohistochemical expression in esophageal cancer: A meta-analysis of the literature. Medicine 2018;97:e11614.
68. Zhang J, Shi Z, Xu X, Yu Z, Mi J. The influence of microenvironment on tumor immunotherapy. FEBS J 2019;286:4160-75.
69. Romero-Garcia S, Moreno-Altamirano MM, Prado-Garcia H, Sánchez-García FJ. Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front Immunol 2016;7:52.
70. Beuselinck B, Job S, Becht E, et al. Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting. Clin Cancer Res 2015;21:1329-39.
71. Epaillard N, Simonaggio A, Elaidi R, et al. BIONIKK: A phase 2 biomarker driven trial with nivolumab and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer. Bull Cancer 2020;107:eS22-7.
72. Meylan M, Sun C, Elaidi R, et al. 1451MO In-situ immune markers predict nivolumab (N)+/-ipilimumab (I) efficacy in frontline metastatic clear cell renal cell carcinoma (mccRCC): Key ancillary analyses from the BIONIKK randomized trial. Annals of Oncolog 2022;33:S1207.
73. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 2018;24:749-57.
74. Rini BI, Powles T, Atkins MB, et al. IMmotion151 study group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet 2019;393:2404-15.
75. Motzer RJ, Banchereau R, Hamidi H, et al. Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. Cancer Cell 2020;38:803-817.e4.
76. Hamieh L, Beck RL, Le VH, Hsieh JJ. The Efficacy of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma exhibiting primary resistance to front-line targeted therapy or immunotherapy. Clin Genitourin Cancer 2020;18:252-257.e2.
77. Santoni M, Aurilio G, Massari F, et al. Nivolumab VERSUS cabozantinib as second-line therapy in patients with advanced renal cell carcinoma: a real-world comparison. Clin Genitourin Cancer 2022;20:285-95.
78. Pal SK, McGregor B, Suárez C, et al. Cabozantinib in combination with atezolizumab for advanced renal cell carcinoma: results from the COSMIC-021 study. J Clin Oncol 2021;39:3725-36.
79. Cannarile MA, Weisser M, Jacob W, Jegg AM, Ries CH, Rüttinger D. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J Immunother Cancer 2017;5:53.
80. Seeber A, Klinglmair G, Fritz J, et al. High IDO-1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma. Cancer Sci 2018;109:1583-91.
81. Mitchell TC, Hamid O, Smith DC, 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;36:3223-30.
82. Long GV, Dummer R, Hamid O, 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.
83. Corrales L, Glickman LH, McWhirter SM, 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.
84. Poeck H, Besch R, Maihoefer C, et al. 5'-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat Med 2008;14:1256-63.
85. Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med 2021;27:802-5.
86. Choueiri TK, McDermott DF, Merchan J, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol 2023;24:553-62.
87. Rini BI, Appleman LJ, Figlin RA, et al. Results from a phase I expansion cohort of the first-in-class oral HIF-2α inhibitor PT2385 in combination with nivolumab in patients with previously treated advanced RCC. J Clin Oncol 2019;37:558-558.
88. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med 1982;155:1823-41.
90. Chatzkel JA, Swank J, Ludlow S, et al. Overall responses with coordinated pembrolizumab and high dose IL-2 (5-in-a-row schedule) for therapy of metastatic clear cell renal cancer: A single center, single arm trial. J Clin Oncol 2019;37:7_suppl, 657-657.
91. Diab A, Hurwitz ME, Cho DC, et al. NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: Preliminary phase 1/2 results of PIVOT. J Clin Oncol 2018;36:3006-3006.
92. Dizman N, Meza L, Bergerot P, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med 2022;28:704-12.
93. 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.
94. Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359:104-8.
95. Cortellini A, Bozzetti F, Palumbo P, et al. Weighing the role of skeletal muscle mass and muscle density in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: a multicenter real-life study. Sci Rep 2020;10:1456.
96. Jerby-Arnon L, Shah P, Cuoco MS, et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 2018;175:984-997.e24.
97. Deng J, Wang ES, Jenkins RW, et al. CDK4/6 Inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov 2018;8:216-33.
98. Sade-Feldman M, Jiao YJ, Chen JH, et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun 2017;8:1136.