Abstract
Immunotherapies, such as immune checkpoint inhibitors, have heralded impressive progress for patient care in renal cell carcinoma (RCC). Despite this success, some patients' disease fails to respond, and other patients experience significant side effects. Thus, development of biomarkers is needed to ensure that patients can be selected to maximize benefit from immunotherapies. Improving clinicians' ability to predict which patients will respond to immunotherapy and which are most at risk of adverse events – namely through clinical biomarkers – is indispensable for patient safety and therapeutic efficacy. Accordingly, an evolving suite of therapeutic biomarkers continues to be investigated. This review discusses biomarkers for immunotherapy in RCC, highlighting current practices and emerging innovations, aiming to contribute to improved outcomes for patients with RCC.
Plain language summary
Renal cell carcinoma (RCC) is a type of kidney cancer. Treatments that target the body's immune system, called immunotherapies, are generally effective in RCC, but not all patients' cancer will respond (shrink or disappear) after receiving this treatment. Because of this, signals, called biomarkers, are needed to signal which patients' cancer will respond and which patients may experience unwanted side effects after treatment. This article highlights biomarkers that have been or are being studied for understanding immunotherapy in RCC.
Graphical abstract
Papers of special note have been highlighted as: • of interest
References
- 1. . Biomarkers for immune checkpoint inhibitors in renal cell carcinoma. J. Clin. Med. 12(15), 4987 (2023).
- 2. Multilevel genomics-based taxonomy of renal cell carcinoma. Cell. Rep. 14(10), 2476–2489 (2016).
- 3. Inhibition of the VEGF/VEGFR pathway improves survival in advanced kidney cancer: a systematic review and meta-analysis. Curr. Drug Targets 16(2), 164–170 (2015).
- 4. . Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 10(10), 992–1000 (2009).
- 5. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373(19), 1803–1813 (2015).
- 6. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378(14), 1277–1290 (2018).
- 7. Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. J Immunother Cancer 9(2), (2021).
- 8. . Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann. Oncol. 27(3), 409–416 (2016).
- 9. . Roles of PD-1/PD-L1 pathway: signaling, cancer, and beyond. Adv. Exp. Med. Biol. 1248, 33–59 (2020).
- 10. . Biomarkers of response to PD-1/PD-L1 inhibition. Crit. Rev. Oncol. Hematol. 116, 116–124 (2017).
- 11. . PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4), 847–856 (2015).
- 12. . Checkpoint inhibitor immunotherapy in kidney cancer. Nat Rev Urol 17(3), 137–150 (2020).
- 13. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N. Engl. J. Med. 379(21), 2040–2051 (2018).
- 14. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372(4), 320–330 (2015).
- 15. Nivolumab plus Cabozantinib versus Sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 384(9), 829–841 (2021).
- 16. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51(2), 202–206 (2019).
- 17. . Finding predictive factors for immunotherapy in metastatic renal-cell carcinoma: what are we looking for? Cancer Treat. Rev. 94, 102157 (2021).
- 18. Molecular and Metabolic Subtypes in Sporadic and Inherited Clear Cell Renal Cell Carcinoma. Genes (Basel) 12(3), 388 (2021).
- 19. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366(26), 2443–2454 (2012).
- 20. Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumors: a guide to immunohistochemistry implementation and interpretation. Pathology 53(2), 141–156 (2021).
- 21. Programmed cell death 1 (PD-1) ligand (PD-L1) expression in solid tumors as a predictive biomarker of benefit from PD-1/PD-L1 axis inhibitors: a systematic review and meta-analysis. JCO Precis Oncol. 1, 1–15 (2017).
- 22. The value of PD-L1 expression as predictive biomarker in metastatic renal cell carcinoma patients: a meta-analysis of randomized clinical trials. Cancers (Basel) 12(7), 1945 (2020).
- 23. Lenvatinib plus Pembrolizumab or Everolimus for advanced renal cell carcinoma. N. Engl. J. Med. 384(14), 1289–1300 (2021).
- 24. Differential expression of PD-L1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol. Res. 3(10), 1158–1164 (2015).
- 25. Nivolumab for metastatic renal cell carcinoma: results of a randomized Phase II trial. J. Clin. Oncol. 33(13), 1430–1437 (2015).
- 26. PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. Clin. Cancer Res. 23(12), 3158–3167 (2017).
- 27. 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 393(10189), 2404–2415 (2019).
- 28. . Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N. Engl. J. Med. 377(25), 2500–2501 (2017).
- 29. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nat. Med. 26(11), 1733–1741 (2020).
- 30. The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What's the Story Morning Glory? Int. J. Mol. Sci. 22(12), 6237 (2021).
- 31. Renal Cell Carcinoma with Sarcomatoid Features: Finally New Therapeutic Hope? Cancers (Basel) 11(3), (2019).
- 32. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 20(10), 1370–1385 (2019). • A study defining the association of sarcomatoid differentiation with enhanced responsiveness to immunotherapy.
- 33. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 21(12), 1563–1573 (2020).
- 34. Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma. Clin. Cancer Res. 27(1), 78–86 (2021).
- 35. Identification of gene signature for treatment response to guide precision oncology in clear-cell renal cell carcinoma. Sci. Rep. 10(1), 2026 (2020).
- 36. Eosinophilic features in clear cell renal cell carcinoma correlate with outcomes of immune checkpoint and angiogenesis blockade. J. Immunother. Cancer 9(9), e002922 (2021).
- 37. . Biomarkers in renal cell carcinoma: are we there yet? Asian J. Urol. 8(4), 362–375 (2021).
- 38. Somatic mutations as preoperative predictors of metastases in patients with localized clear cell renal cell carcinoma - an exploratory analysis. Urol. Oncol. 39(11), 791.e717–791.e724 (2021).
- 39. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469(7331), 539–542 (2011).
- 40. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359(6377), 801–806 (2018).
- 41. Clinical Validation of PBRM1 Alterations as a Marker of Immune Checkpoint Inhibitor Response in Renal Cell Carcinoma. JAMA Oncol. 5(11), 1631–1633 (2019).
- 42. PBRM1 mutation as a predictive biomarker for immunotherapy in multiple cancers. Front. Genet. 13, 1066347 (2022).
- 43. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol. 14(2), 159–167 (2013).
- 44. Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma. Cancer 120(7), 1059–1067 (2014).
- 45. . Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma. J. Exp. Clin. Cancer Res. 40(1), 254 (2021).
- 46. . Resistance to cancer immunotherapy in metastatic renal cell carcinoma. Cancer Drug Resist. 3(3), 454–471 (2020).
- 47. Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. Lancet Oncol. 19(12), 1688–1698 (2018).
- 48. . Histone methyltransferase SETD2: a potential tumor suppressor in solid cancers. J. Cancer 11(11), 3349–3356 (2020).
- 49. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin. Cancer Res. 19(12), 3259–3267 (2013).
- 50. SETD2 variation correlates with tumor mutational burden and MSI along with improved response to immunotherapy. BMC Cancer 23(1), 686 (2023).
- 51. . Bioinformatics profiling integrating a four immune-related long non-coding RNAs signature as a prognostic model for papillary renal cell carcinoma. Aging (Albany NY) 12(15), 15359–15373 (2020).
- 52. Correlation Between Molecular Subclassifications of Clear Cell Renal Cell Carcinoma and Targeted Therapy Response. Eur. Urol. Focus 2(2), 204–209 (2016).
- 53. . The Significance of PARP1 as a biomarker for Predicting the Response to PD-L1 Blockade in Patients with PBRM1-mutated Clear Cell Renal Cell Carcinoma. Eur. Urol. 81(2), 145–148 (2022).
- 54. . Interrogating the Significance of PARP1 Expression and PBRM1 Mutation as Biomarkers for Predicting the Response to Atezolizumab plus Bevacizumab or to Sunitinib in Patients with Clear Cell Renal Cell Carcinoma. Eur. Urol. 82(3), 334–335 (2022).
- 55. Establishment of a novel gene panel as a biomarker of immune checkpoint inhibitor response. Clin. Transl. Immunol. 9(7), e1145 (2020).
- 56. Impact of DNA Damage Response and Repair (DDR) Gene Mutations on Efficacy of PD-(L)1 Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer. Clin. Cancer Res. 26(15), 4135–4142 (2020).
- 57. 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. 36(7), 633–641 (2018).
- 58. Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma. J. Immunother. Cancer 8(1), e000319 (2020).
- 59. . New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13(7), 411–424 (2012).
- 60. The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma. Front. Oncol. 11, 681441 (2021).
- 61. ORCHID: a phase II study of Olaparib in Metastatic Renal Cell Carcinoma Patients HarborIng a BAP1 or Other DNA Repair Gene Mutations. Oncologist 28(Suppl. 1), S1 (2023).
- 62. TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas. Oncoimmunology 7(7), e1442999 (2018).
- 63. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576(7787), 465–470 (2019).
- 64. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553(7688), 347–350 (2018).
- 65. . Immunotherapy for hepatocellular carcinoma: current and future. World J. Gastroenterol. 25(24), 2977–2989 (2019).
- 66. . Importance of Multiparametric Evaluation of Immune-Related T-Cell Markers in Renal-Cell Carcinoma. Clin. Genitourin. Cancer 17(6), e1147–e1152 (2019).
- 67. Immune infiltration in renal cell carcinoma. Cancer Sci. 110(5), 1564–1572 (2019).
- 68. . Checkpoint molecule PD-1-assisted CD8(+) T lymphocyte count in tumor microenvironment predicts overall survival of patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. Cancer Manag. Res. 10, 3419–3431 (2018).
- 69. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res. 61(13), 5132–5136 (2001).
- 70. Clinical outcome following checkpoint therapy in renal cell carcinoma is associated with a burst of activated CD8 T cells in blood. J. Immunother. Cancer 10(7), (2022). • A study describing a peripheral burst of activated CD8 T cells in patients with positive response to immunotherapy, as well as increased presence of intratumoral immune niches in patients with clinical benefit following immunotherapy.
- 71. Prognostic and Predictive Value of Tumor-infiltrating Leukocytes and of Immune Checkpoint Molecules PD1 and PDL1 in Clear Cell Renal Cell Carcinoma. Transl. Oncol. 13(2), 336–345 (2020).
- 72. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362(6411), eaar3593 (2018).
- 73. The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Anti-PD-1 Response in Patients with Renal Cell Carcinoma. Cancer Immunol. Res. 4(9), 726–733 (2016).
- 74. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat. Commun. 7, 12624 (2016).
- 75. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359(6371), 91–97 (2018).
- 76. Stool Microbiome Profiling of Patients with Metastatic Renal Cell Carcinoma Receiving Anti-PD-1 Immune Checkpoint Inhibitors. Eur. Urol. 78(4), 498–502 (2020).
- 77. Stool Bacteriomic Profiling in Patients with Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitors. Clin. Cancer Res. 21(23), 5286–5293 (2015).
- 78. 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. 29(6), 1437–1444 (2018).
- 79. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat. Med. 28(4), 704–712 (2022).
- 80. . The scent of disease: volatile organic compounds of the human body related to disease and disorder. J. Biochem. 150(3), 257–266 (2011).
- 81. . Clinical use of exhaled volatile organic compounds in pulmonary diseases: a systematic review. Respir. Res. 13(1), 117 (2012).
- 82. . Digging deeper into volatile organic compounds associated with cancer. Biol. Methods Protoc. 4(1), bpz014 (2019).
- 83. . Biomarkers for early diagnosis of malignant mesothelioma: do we need another moonshot? Oncotarget 8(32), 53751–53762 (2017).
- 84. . Accuracy and Methodologic Challenges of Volatile Organic Compound-Based Exhaled Breath Tests for Cancer Diagnosis: A Systematic Review and Meta-analysis. JAMA Oncol. 5(1), e182815 (2019).
- 85. Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath. Ann. Oncol. 30(10), 1660–1666 (2019).
- 86. eNose analysis for early immunotherapy response monitoring in non-small cell lung cancer. Lung Cancer 160, 36–43 (2021).
- 87. Breathomics as Predictive Biomarker for Checkpoint Inhibitor Response. https://clinicaltrials.gov/study/NCT04146064
- 88. . Urinary VOCs as bladder cancer biomarkers. Nat. Rev. Urol. 19(5), 256 (2022).
- 89. Urine LOX-1 and Volatilome as Promising Tools towards the Early Detection of Renal Cancer. Cancers (Basel) 13(16), (2021).
- 90. . Unlocking the secret of the obesity paradox in renal tumors. Lancet Oncol. 21(2), 194–196 (2020).
- 91. Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ Programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: a multicentre analysis of immune-related adverse events. Eur. J. Cancer 128, 17–26 (2020).
- 92. Transcriptomic signatures related to the obesity paradox in patients with clear cell renal cell carcinoma: a cohort study. Lancet Oncol. 21(2), 283–293 (2020).
- 93. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat. Med. 25(1), 141–151 (2019).
- 94. Impact of BMI on Survival Outcomes of Immunotherapy in Solid Tumors: A Systematic Review. Int. J. Mol. Sci. 22(5), 2628 (2021).
- 95. Body Composition as an Independent Predictive and Prognostic Biomarker in Advanced Urothelial Carcinoma Patients Treated with Immune Checkpoint Inhibitors. Oncologist 26(12), 1017–1025 (2021). • A study describing the potential of use of immune-related adverse events (irAE) occurrence as a clinical biomarker of therapeutic response to immune checkpoint blockade in patients with metastatic renal cell carcinoma.
- 96. Body Composition Variables as Radiographic Biomarkers of Clinical Outcomes in Metastatic Renal Cell Carcinoma Patients Receiving Immune Checkpoint Inhibitors. Front. Oncol. 11, 707050 (2021).
- 97. Adiposity may predict survival in patients with advanced stage cancer treated with immunotherapy in phase 1 clinical trials. Cancer 126(3), 575–582 (2020).
- 98. Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy. Oncologist 25(3), e528–e535 (2020).
- 99. Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 106, 1–7 (2017).
- 100. Prognostic impact of neutrophil-to-lymphocyte ratio in renal cell carcinoma: a systematic review and meta-analysis. Immunotherapy 11(7), 631–643 (2019).
- 101. Change in Neutrophil-to-lymphocyte Ratio in Response to Targeted Therapy for Metastatic Renal Cell Carcinoma as a Prognosticator and Biomarker of Efficacy. Eur. Urol. 70(2), 358–364 (2016).
- 102. Change in Neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J. Immunother. Cancer 6(1), 5 (2018).
- 103. . Prognostic value of pretreatment neutrophil-to-lymphocyte ratio in renal cell carcinoma: a systematic review and meta-analysis. BMC Urol. 20(1), 90 (2020).
- 104. Association of Neutrophil-to-Lymphocyte Ratio with Efficacy of First-Line Avelumab plus Axitinib vs. Sunitinib in Patients with Advanced Renal Cell Carcinoma Enrolled in the Phase 3 JAVELIN Renal 101 Trial. Clin. Cancer Res. 28(4), 738–747 (2022).
- 105. Association Between Pretreatment Neutrophil-to-Lymphocyte Ratio and Outcome of Patients With Metastatic Renal-Cell Carcinoma Treated With Nivolumab. Clin. Genitourin. Cancer 16(3), e563–e575 (2018).
- 106. . Inflammatory Markers in Cancer Immunotherapy. Biology (Basel) 10(4), (2021).
- 107. The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy. Cancer 125(1), 127–134 (2019).
- 108. Novel risk scoring system for metastatic renal cell carcinoma patients treated with cabozantinib. Cancer Treat. Res. Commun. 28, 100393 (2021).
- 109. Baseline Neutrophil-to-Eosinophil Ratio Is Associated with Outcomes in Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors. Oncologist 28(3), 239–245 (2023).
- 110. Modified Glasgow Prognostic Score associated with survival in metastatic renal cell carcinoma treated with immune checkpoint inhibitors. J. Immunother. Cancer 9(7), e002851 (2021).
- 111. Novel Risk Scoring System for Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors. Oncologist 25(3), e484–e491 (2020).
- 112. Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors. Genome Med. 12(1), 23 (2020).
- 113. . Circulating Tumor DNA in Patients with Renal Cell Carcinoma. A Systematic Review of the Literature. Eur. Urol. Open Sci. 37, 27–35 (2022).
- 114. Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications. Oncotarget 8(20), 33614–33620 (2017).
- 115. Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma. Eur. Urol. 72(4), 557–564 (2017).
- 116. . Liquid biopsy: current technology and clinical applications. J. Hematol. Oncol. 15(1), 131 (2022).
- 117. Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov. 10(12), 1842–1853 (2020).
- 118. CircRNAs in cancer metabolism: a review. J. Hematol. Oncol. 12(1), 90 (2019).
- 119. The emerging functions and roles of circular RNAs in cancer. Cancer Lett. 414, 301–309 (2018).
- 120. Circular RNAs as prognostic and diagnostic biomarkers in renal cell carcinoma. J. Clin. Lab. Anal. 36(10), e24670 (2022).
- 121. Identification of CircRNA signature associated with tumor immune infiltration to predict therapeutic efficacy of immunotherapy. Nat. Commun. 14(1), 2540 (2023).
- 122. Circular RNAs in Clear Cell Renal Cell Carcinoma: Their Microarray-Based Identification, Analytical Validation, and Potential Use in a Clinico-Genomic Model to Improve Prognostic Accuracy. Cancers (Basel) 11(10), 1473 (2019).
- 123. Emerging function and potential diagnostic value of circular RNAs in cancer. Mol. Cancer 17(1), 123 (2018).
- 124. . Aberration of lncRNA LINC00460 is a Promising Prognosis Factor and Associated with Progression of Clear Cell Renal Cell Carcinoma. Cancer Manag. Res. 13, 6489–6497 (2021).
- 125. . The long non-coding RNA NNT-AS1 promotes clear cell renal cell carcinoma progression via regulation of the miR-137/ Y-box binding protein 1 axis. Bioengineered 12(1), 8994–9005 (2021).
- 126. Identification of a Three-Glycolysis-Related lncRNA Signature Correlated With Prognosis and Metastasis in Clear Cell Renal Cell Carcinoma. Front. Med. (Lausanne) 8, 777507 (2021).
- 127. Construction of Competitive Endogenous RNA Network and Verification of 3-Key LncRNA Signature Associated With Distant Metastasis and Poor Prognosis in Patients With Clear Cell Renal Cell Carcinoma. Front. Oncol. 11, 640150 (2021).
- 128. . MALAT1: a long non-coding RNA highly associated with human cancers. Oncol. Lett. 16(1), 19–26 (2018).
- 129. Long Noncoding RNA MALAT1 Promotes Aggressive Renal Cell Carcinoma through Ezh2 and Interacts with miR-205. Cancer Res. 75(7), 1322–1331 (2015).
- 130. MiR-532-5p suppresses renal cancer cell proliferation by disrupting the ETS1-mediated positive feedback loop with the KRAS-NAP1L1/P-ERK axis. Br. J. Cancer 119(5), 591–604 (2018).
- 131. Mechanism of tumor-derived extracellular vesicles in regulating renal cell carcinoma progression by the delivery of MALAT1. Oncol. Rep. 46(3), 187 (2021).
- 132. . Long non-coding RNA MALAT1 correlates with cell viability and mobility by targeting miR-22-3p in renal cell carcinoma via the PI3K/Akt pathway. Oncol. Rep. 41(2), 1113–1121 (2019).
- 133. LncRNA RCAT1 promotes tumor progression and metastasis via miR-214-5p/E2F2 axis in renal cell carcinoma. Cell Death Dis. 12(7), 689 (2021).
- 134. N6-Methyladenosine Modification of LncRNA DUXAP9 Promotes Renal Cancer Cells Proliferation and Motility by Activating the PI3K/AKT Signaling Pathway. Front. Oncol. 11, 641833 (2021).
- 135. AGAP2-AS1 as a prognostic biomarker in low-risk clear cell renal cell carcinoma patients with progressing disease. Cancer Cell Int. 21(1), 690 (2021).
- 136. Prognostic Value of Long Noncoding RNA DLEU2 and Its Relationship with Immune Infiltration in Kidney Renal Clear Cell Carcinoma and Liver Hepatocellular Carcinoma. Int. J. Gen. Med. 14, 8047–8064 (2021).
- 137. lncRNA DLEU2 promotes gastric cancer progression through ETS2 via targeting miR-30a-5p. Cancer Cell Int. 21(1), 376 (2021).
- 138. Long non-coding RNA DLEU2 drives EMT and glycolysis in endometrial cancer through HK2 by competitively binding with miR-455 and by modulating the EZH2/miR-181a pathway. J. Exp. Clin. Cancer Res. 40(1), 216 (2021).
- 139. Long non-coding RNA linc00460 promotes epithelial-mesenchymal transition and cell migration in lung cancer cells. Cancer Lett. 420, 80–90 (2018).
- 140. . Effects of Linc00460 on cell migration and invasion through regulating epithelial-mesenchymal transition (EMT) in non-small cell lung cancer. Eur. Rev. Med. Pharmacol. Sci. 22(4), 1003–1010 (2018).
- 141. LINC00460-miR-149-5p/miR-150-5p-Mutant p53 Feedback Loop Promotes Oxaliplatin Resistance in Colorectal Cancer. Mol. Ther. Nucleic Acids 22, 1004–1015 (2020).
- 142. Association of Long Noncoding RNA Biomarkers With Clinical Immune Subtype and Prediction of Immunotherapy Response in Patients With Cancer. JAMA Netw. Open 3(4), e202149 (2020).
- 143. Combinatorial biomarker for predicting outcomes to anti-PD-1 therapy in patients with metastatic clear cell renal cell carcinoma. Cell Rep. Med. 4(2), 100947 (2023). • A study proposing a multimodal approach to biomarker development, combining histology-based measurement of lymphocyte infiltration, presence of necrosis and PBRM1 mutational status.
- 144. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24(6), 749–757 (2018).
- 145. Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma. Cancer Cell 39(5), 649–661.e645 (2021).
- 146. . Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J. Immunother. Cancer 7(1), 306 (2019).
- 147. Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study. Clin. Genitourin. Cancer
doi: 10.1016/j.clgc.2023.09.007 (2023). - 148. Immune-related adverse events are clinical biomarkers to predict favorable outcomes in advanced renal cell carcinoma treated with nivolumab plus ipilimumab. Jpn. J. Clin. Oncol. 52(5), 479–485 (2022).
- 149. Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors. Oncologist 26(10), e1742–e1750 (2021). • A study describing the potential of use of irAE occurrence as a clinical biomarker of therapeutic response to immune checkpoint blockade in patients with metastatic renal cell carcinoma.
- 150. Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis. Int. J. Clin. Oncol. 28(12), 1651–1658 (2023).
- 151. . Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors. Oncotarget 8(69), 114268–114280 (2017).
- 152. . Absolute eosinophil count may be an optimal peripheral blood marker to identify the risk of immune-related adverse events in advanced malignant tumors treated with PD-1/PD-L1 inhibitors: a retrospective analysis. World J. Surg. Oncol. 20(1), 242 (2022).
- 153. Elevated eosinophils proportion as predictor of immune-related adverse events after ipilimumab and nivolumab treatment of advanced and metastatic renal cell carcinoma. Int. J. Urol. 30(10), 866–874 (2023).
- 154. The determinants of very severe immune-related adverse events associated with immune checkpoint inhibitors: a prospective study of the French REISAMIC registry. Eur. J. Cancer 158, 217–224 (2021).
- 155. . Association of blood biomarkers and autoimmunity with immune related adverse events in patients with cancer treated with immune checkpoint inhibitors. Sci. Rep. 11(1), 9029 (2021).
- 156. Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab. Sci. Rep. 9(1), 14039 (2019).
- 157. . Risk factors for adverse events induced by immune checkpoint inhibitors in patients with non-small-cell lung cancer: a systematic review and meta-analysis. Cancer Immunol. Immunother. 70(11), 3069–3080 (2021).
- 158. Neutrophil-to-Lymphocyte Ratio Predicts Development of Immune-Related Adverse Events and Outcomes from Immune Checkpoint Blockade: A Case-Control Study. Cancers (Basel) 13(6), 1308 (2021).
- 159. Identifying Early Predictive Markers for Immune-Related Adverse Events in Nivolumab-Treated Patients with Renal Cell Carcinoma and Gastric Cancer. Asian Pac. J. Cancer Prev. 23(2), 695–701 (2022).
- 160. 142P The predictive biomarker for immune-related adverse events (irAEs) in patients with metastatic renal cell carcinoma treated with the combination therapy of nivolumab plus ipilimumab: musashino study-irAE. Ann. Oncol. 33, S1488 (2022).
- 161. Immune dysregulation in cancer patients developing immune-related adverse events. Br. J. Cancer 120(1), 63–68 (2019).
- 162. Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities. Proc. Natl Acad. Sci. USA 116(44), 22246–22251 (2019).
- 163. Association of immune-related adverse events induced by nivolumab with a battery of autoantibodies. Ann. Med. 53(1), 762–769 (2021).
- 164. Evaluation of autoantibodies as predictors of treatment response and immune-related adverse events during the treatment with immune checkpoint inhibitors: a prospective longitudinal pan-cancer study. Cancer Med. 11(16), 3074–3083 (2022).
- 165. Single-cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors. Cell Rep. Med. 4(1), 100868 (2023).
- 166. T-Cell Receptor Repertoire as a Predictor of Immune-Related Adverse Events in Renal Cell Carcinoma. Curr. Issues Mol. Biol. 45(11), 8939–8949 (2023).
- 167. Prior Anti-Angiogenic TKI-Based Treatment as Potential Predisposing Factor to Nivolumab-Mediated Recurrent Thyroid Disorder Adverse Events in mRCC Patients: A Case Series. Biomedicines 11(11), 2974 (2023).
- 168. . Case Report: successful immune checkpoint inhibitor-based rechallenge in a patient with advanced renal clear cell cancer. Front. Immunol. 14, 1270828 (2023).