2024
PAK4-targeted PROTACs in clear cell renal cell carcinoma: a two-for-one targeted and immune therapy?
Bakouny Z, Braun D, Reznik E, Hakimi A. PAK4-targeted PROTACs in clear cell renal cell carcinoma: a two-for-one targeted and immune therapy? EBioMedicine 2024, 105: 105218. PMID: 38924842, DOI: 10.1016/j.ebiom.2024.105218.Peer-Reviewed Original ResearchEpigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma
El Zarif T, Semaan K, Eid M, Seo J, Garinet S, Davidsohn M, Sahgal P, Fortunato B, Canniff J, Nassar A, Abou Alaiwi S, Bakouny Z, Lakshminarayanan G, Savignano H, Lyons K, Matar S, Ali A, Saad E, Saliby R, Cordeiro P, Zhang Z, El Ahmar N, Laimon Y, Labaki C, Shah V, Freeman D, O'Toole J, Lee G, Hwang J, Pomerantz M, Signoretti S, Van Allen E, Xie W, Berchuck J, Viswanathan S, Braun D, Choueiri T, Freedman M, Baca S. Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma. Cell Reports 2024, 43: 114350. PMID: 38870013, DOI: 10.1016/j.celrep.2024.114350.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsRenal cell carcinomaSarcomatoid differentiationCell carcinomaResponse to immune checkpoint inhibitorsGene regulatory programsAssociated with poor survivalTreatment of renal cell carcinomaLow diagnostic yieldRandomized clinical trialsCheckpoint inhibitorsTumor histologyEpigenomic signaturesTranscription factor FOSL1Healthy volunteersPatient plasmaPoor survivalLiquid biopsyFOSL1 expressionClinical trialsProfiling histone modificationsDiagnostic approachImprove outcomesRegulatory programsPlasma samplesEmerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy.
Ali M, Eid M, Saliby R, Choi S, McKay R, Siva S, Braun D, Chen Y. Emerging Novel Functional Imaging and Immunotherapy in Renal Cell Carcinoma and Current Treatment Sequencing Strategies After Immunotherapy. American Society Of Clinical Oncology Educational Book 2024, 44: e438658. PMID: 38875505, DOI: 10.1200/edbk_438658.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaTreatment sequencing strategiesCell carcinomaImmune checkpoint inhibitors targeting PD-1Chimeric antigen receptor T-cell therapyCheckpoint inhibitors targeting PD-1Management of renal cell carcinomaAdvanced renal cell carcinomaProstate-specific membrane antigenLandscape of renal cell carcinomaRCC-associated antigensImmune checkpoint inhibitionT-cell therapyPrimary kidney tumorsAssess treatment responseChanging treatment landscapeCarbonic anhydrase IXFunctional imagingFunctional imaging modalitiesCheckpoint inhibitionPD-1Immunotherapy strategiesLAG-3Membrane antigenT cellsInvestigation of T cell phenotypes associated with response or resistance to immune checkpoint inhibitors (ICI) through single-cell analysis of renal cell carcinoma (RCC).
Kashima S, Ye Z, Meliki A, Hugaboom M, Schindler N, Graham J, Moritz V, El Ahmar N, Nabil Laimon Y, Canniff J, Saliby R, Lee G, Machaalani M, Sun M, Xu W, Signoretti S, McGregor B, McKay R, CHOUEIRI T, Braun D. Investigation of T cell phenotypes associated with response or resistance to immune checkpoint inhibitors (ICI) through single-cell analysis of renal cell carcinoma (RCC). Journal Of Clinical Oncology 2024, 42: 4515-4515. DOI: 10.1200/jco.2024.42.16_suppl.4515.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsRenal cell carcinomaCD8+ T cell infiltrationT cell infiltrationNon-respondersTumor microenvironmentT cellsRCC tumor microenvironmentResistance to immune checkpoint inhibitorsICI responseImmune checkpoint inhibitor treatmentImmune checkpoint inhibitor efficacyCD8+ T cellsExpressed PD-1ICI-treated patientsGene programGene signature scoresTumor mutation loadCellular compositionGene expression signaturesSingle-cell transcriptome analysisCheckpoint inhibitorsPD-1Partial responseSystemic therapyCharacterizing genomic alterations in patients with metastatic urothelial carcinoma (mUC) treated with enfortumab-vedotin (EV) with a focus on 1q23.3.
Saliby R, Semaan K, Epstein I, Liria S, Dall C, Saad E, Eid M, Canniff J, Kwak L, Berg S, Mantia C, McGregor B, Braun D, CHOUEIRI T, Bellmunt J. Characterizing genomic alterations in patients with metastatic urothelial carcinoma (mUC) treated with enfortumab-vedotin (EV) with a focus on 1q23.3. Journal Of Clinical Oncology 2024, 42: e16570-e16570. DOI: 10.1200/jco.2024.42.16_suppl.e16570.Peer-Reviewed Original ResearchMetastatic urothelial carcinomaToxicity-free survivalProgression-free survivalEnfortumab vedotinOverall survivalProgressive diseaseTwo-copy deletionGenomic alterationsClinical outcomesAssociation of genomic alterationsNumerically longer OSDana-Farber Cancer InstituteLog-rank testFisher's exact testUnivariate Cox regressionAdvanced UCLonger OSUrothelial carcinomaSomatic alterationsDana-FarberExact testCox regressionEV efficacyPatientsImprove outcomesApplying genomic analysis to refine unclassified renal cell carcinoma.
Yekeduz E, Braun D, El Hajj Chehade R, Eid M, Labaki C, Machaalani M, Nassar A, Nawfal R, Saad E, Saliby R, Semaan K, Sun M, Hirsch M, Ürün Y, El Zarif T, CHOUEIRI T. Applying genomic analysis to refine unclassified renal cell carcinoma. Journal Of Clinical Oncology 2024, 42: 4551-4551. DOI: 10.1200/jco.2024.42.16_suppl.4551.Peer-Reviewed Original ResearchRenal cell carcinomaClear cell RCCRenal cell carcinoma subtypesAmerican Association for Cancer ResearchPapillary RCCGenomic alterationsOverall survivalCell carcinomaGenomic profilingPapillary renal cell carcinomaSubtype of renal cell carcinomaChromophobe renal cell carcinomaProportion of female patientsClear cell renal cell carcinomaMedian overall survivalCell renal cell carcinomaCo-mutated genesCompare categorical variablesBenjamini-Hochberg correctionOncogenic signaling pathwaysMetastatic sitesFrequent subtype of renal cell carcinomaPrimary tumorChi-square testNF2 alterationsMolecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC).
Zaemes J, Hugaboom M, Shah V, Haas N, McDermott D, Jegede O, Bilen M, Stein M, Sosman J, Alter R, Plimack E, Hurwitz M, Wu C, Einstein D, Hammers H, Signoretti S, West D, Denize T, Atkins M, Braun D. Molecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC). Journal Of Clinical Oncology 2024, 42: 4546-4546. DOI: 10.1200/jco.2024.42.16_suppl.4546.Peer-Reviewed Original ResearchObjective response rateImmune checkpoint blockadeProgression-free survivalProgressive diseaseAnti-VEGFOverall survivalAssociated with higher progression-free survivalTumor samplesAdvanced clear cell renal cell carcinomaCombined immune checkpoint blockadeHigher progression-free survivalIncreased PFSImmune checkpoint blockade therapyShorter progression-free survivalClear cell renal cell carcinomaAnti-VEGF therapyCell renal cell carcinomaWeeks of therapyRenal cell carcinomaBiomarkers of efficacyFFPE tumor samplesNIVO monotherapyCheckpoint blockadeDecreased OSProspective trialsExpression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial.
Nabil Laimon Y, Paul M, Ghandour F, El Ahmar N, Matar S, Denize T, Bagheri Sheshdeh A, Savla V, Mohanna R, Sun M, Saliby R, Saad E, Machaalani M, Braun D, Aftab D, Xie W, CHOUEIRI T, Signoretti S. Expression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial. Journal Of Clinical Oncology 2024, 42: 4543-4543. DOI: 10.1200/jco.2024.42.16_suppl.4543.Peer-Reviewed Original ResearchProgression-free survivalAssociated with progression-free survivalReceptor tyrosine kinase AXLTyrosine kinase inhibitorsRenal cell carcinomaImmune cellsMETEOR trialTyrosine kinase AXLAxl expressionTumor cellsCell carcinomaAssociated with shorter progression-free survivalMetastatic clear cell renal cell carcinomaAnti-PD-1 therapyLevels of AXL expressionMetastatic renal cell carcinomaMultitargeted tyrosine kinase inhibitorPresence of bone metastasesShorter progression-free survivalClear cell renal cell carcinomaIMDC risk groupsPretreatment tumor tissueVEGFR-TKI treatmentCell renal cell carcinomaDouble immunohistochemistry stainingAdvanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Serzan M, Jegede O, Alter R, Bilen M, Braun D, Einstein D, Haas N, Herchenhorn D, King J, Runcie K, Sosman J, Sternberg C, Yang Y, Signoretti S, CHOUEIRI T, Atkins M. Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587). Journal Of Clinical Oncology 2024, 42: tps4614-tps4614. DOI: 10.1200/jco.2024.42.16_suppl.tps4614.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsArm BArm APrimary endpointRate of immune-related adverse eventsMetastatic clear cell renal cell carcinomaImmune-related adverse eventsMolecular predictors of responseVEGF receptor tyrosine kinase inhibitorReceptor tyrosine kinase inhibitorsEnhance T cell primingOne-sided significance levelClear cell renal cell carcinomaAnti-PD1 inhibitorsIMDC risk groupsTreatment free intervalProgression-free survivalT cell primingTreatment-free survivalCell renal cell carcinomaSubpopulations of TregsFirst-line treatmentRenal cell carcinomaPredictors of responseAssociated with increased presenceIntratumoral T-cell infiltration and response to nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma from the CheckMate-214 trial.
Matar S, Jegede O, Denize T, Ghandour F, Nabil Laimon Y, El Ahmar N, Bagheri Sheshdeh A, Savla V, Mohanna R, Catalano P, Braun D, Sun M, Gupta S, Vemula S, Freeman G, Motzer R, Atkins M, McDermott D, CHOUEIRI T, Signoretti S. Intratumoral T-cell infiltration and response to nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma from the CheckMate-214 trial. Journal Of Clinical Oncology 2024, 42: 4536-4536. DOI: 10.1200/jco.2024.42.16_suppl.4536.Peer-Reviewed Original ResearchProgression-free survivalAssociated with progression-free survivalMultiplex immunofluorescenceClinical trialsClinical outcomesMetastatic clear cell renal cell carcinomaIntratumoral T cell infiltrationTreated with nivolumab monotherapyMetastatic clear cell RCCClear cell renal cell carcinomaResponse to nivolumabT cell infiltrationCell renal cell carcinomaPoor-risk patientsRenal cell carcinomaClear cell RCCFormalin fixed paraffinContinuous variablesNivolumab monotherapyCox proportional hazardsAntigen-experiencedCell RCCCell carcinomaLogistic regression modelsPositive associationImpact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes
Saliby R, Labaki C, Jammihal T, Xie W, Sun M, Shah V, Saad E, Kane M, Kashima S, Sadak K, El Zarif T, Poduval D, Motzer R, Powles T, Rini B, Albiges L, Pal S, McGregor B, McKay R, Signoretti S, Van Allen E, Shukla S, Choueiri T, Braun D. Impact of renal cell carcinoma molecular subtypes on immunotherapy and targeted therapy outcomes. Cancer Cell 2024, 42: 732-735. PMID: 38579722, PMCID: PMC11130783, DOI: 10.1016/j.ccell.2024.03.002.Peer-Reviewed Original ResearchIntegrative Analysis of Germline Rare Variants in Clear and Non–clear Cell Renal Cell Carcinoma
Han S, Camp S, Chu H, Collins R, Gillani R, Park J, Bakouny Z, Ricker C, Reardon B, Moore N, Kofman E, Labaki C, Braun D, Choueiri T, AlDubayan S, Van Allen E. Integrative Analysis of Germline Rare Variants in Clear and Non–clear Cell Renal Cell Carcinoma. European Urology Open Science 2024, 62: 107-122. PMID: 38496821, PMCID: PMC10940785, DOI: 10.1016/j.euros.2024.02.006.Peer-Reviewed Original ResearchCopy number variantsGermline pathogenic variantsCryptic splice variantsNon-clear cell renal cell carcinomaCell renal cell carcinomaRare inherited mutationsRenal cell carcinomaPathogenic variantsSomatic eventsPopulation stratificationRisk of kidney cancerAge of cancer onsetGermline copy number variantsSplice variantsBurden of pathogenic variantsCell carcinomaEstimation of genetic riskRenal cell carcinoma riskRCC patientsCancer-free controlsCase-control analysisCase-control studyRenal cell carcinoma patientsClear cell renal cell carcinomaGermline rare variantsEvaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study.
Saliby R, Xie W, Wells J, Saad E, Eid M, Labaki C, Semaan K, Ferrier E, Lemelin A, Suárez C, Ruiz-Morales J, Powles T, Wood L, Ebrahimi H, de Velasco G, Takemura K, Agarwal N, Braun D, Heng D, Choueiri T. Evaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study. Journal Of Clinical Oncology 2024, 42: 400-400. DOI: 10.1200/jco.2024.42.4_suppl.400.Peer-Reviewed Original ResearchTime to next therapyTime to treatment failureInternational mRCC Database ConsortiumImmune checkpoint inhibitorsMetastatic renal cell carcinomaOverall survivalIntermediate endpointsHazard ratioInternational mRCC Database Consortium risk groupTreated with immune checkpoint inhibitorsDual immune checkpoint inhibitorsICI startICI-based regimensAssociated with OSAssociation of OSEndpoint of OSRenal cell carcinomaCheckpoint inhibitorsNext therapyMetastatic sitesDrug cessationTreatment failurePrimary endpointCell carcinomaMedian ageTumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial.
El Ahmar N, Matar S, Jegede O, Nabil Laimon Y, Savla V, Bagheri Sheshdeh A, Denize T, Mohanna R, Choueiri T, Catalano P, Braun D, Haas N, Hammers H, Bilen M, Stein M, Sosman J, Wu C, McDermott D, Atkins M, Signoretti S. Tumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial. Journal Of Clinical Oncology 2024, 42: 448-448. DOI: 10.1200/jco.2024.42.4_suppl.448.Peer-Reviewed Original ResearchClear cell renal cell carcinomaProgression-free survivalCD163-positive macrophagesTumor areaNivolumab therapyDensity of CD163-positive cellsCD8+ T cell infiltrationAssociated with progression-free survivalResponse to immune checkpoint inhibitorsAdvanced clear cell renal cell carcinomaAnti-PD-1 therapyTumor-infiltrating myeloid cellsProgression-free survival endpointAssociated with poor outcomesFirst-line nivolumabImmune checkpoint inhibitorsMyeloid cell infiltrationT cell infiltrationCell renal cell carcinomaRenal cell carcinomaPrimary tumor tissuesCD163-positive cellsCheckpoint inhibitorsCox proportional hazardsCell carcinomaDetection of sarcomatoid renal cell carcinoma using plasma cell-free DNA methylation.
Semaan K, El Zarif T, Seo J, Eid M, Canniff J, Fortunato B, Savignano H, Davidsohn M, Lakshminarayanan G, Saad E, Saliby R, Bakouny Z, Matar S, Nuzzo P, Berchuck J, Signoretti S, Braun D, Freedman M, Baca S, Choueiri T. Detection of sarcomatoid renal cell carcinoma using plasma cell-free DNA methylation. Journal Of Clinical Oncology 2024, 42: 449-449. DOI: 10.1200/jco.2024.42.4_suppl.449.Peer-Reviewed Original ResearchDifferentially methylated regionsRenal cell carcinomaCell-free DNAMeDIP-seqSarcomatoid differentiationDNA methylation signalsArea under the receiver operating characteristicHigh-throughput sequencingCell carcinomaCell-free DNA methylationFalse discovery rateResponse to immune checkpoint blockadeEpigenomic approachesCfMeDIP-seqSarcomatoid renal cell carcinomaMethylation immunoprecipitationDNA methylationHistological subtypes of cancerAssociated with poor survivalImmune checkpoint blockadeSubtypes of cancerDana-Farber Cancer InstituteSpatial heterogeneityArea under the receiver operating characteristic curveWilcoxon rank sum testMulti-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma.
Saad E, Labaki C, Miron B, Park J, Bakouny Z, Nassar A, Saliby R, Semaan K, Eid M, Meli K, Nabil Laimon Y, Geynisman D, Kokate R, Braun D, Signoretti S, McGregor B, Plimack E, Choueiri T, Van Allen E, Zibelman M. Multi-omic characterization of acquired resistance to immune checkpoint inhibitors in patients with metastatic renal cell carcinoma. Journal Of Clinical Oncology 2024, 42: 459-459. DOI: 10.1200/jco.2024.42.4_suppl.459.Peer-Reviewed Original ResearchMetastatic renal cell carcinomaImmune checkpoint inhibitorsTertiary lymphoid structuresWhole-exome sequencingDifferential gene expression analysisRenal cell carcinomaGene set enrichment analysisCheckpoint inhibitorsCell carcinomaB cellsAbsence of tertiary lymphoid structuresGene mutationsResistance to immune checkpoint inhibitorsPresence of tertiary lymphoid structuresImmune checkpoint inhibitor treatmentRNA-seqInitial response to therapyCD8+ T cell fractionCohort of ptsICI-based regimensDana-Farber Cancer InstituteT cell functionResponse to therapyNaive B cellsT-cell fractionCellular and molecular determinants of limited anti-tumor immunity in chromophobe renal carcinoma (ChRCC).
Labaki C, Alchoueiry M, Bi K, Zhang L, Hobeika C, Bakouny Z, El Ahmar N, Matar S, Priolo C, Khabibullin D, Schindler N, Camp S, Saliby R, Saad E, Signoretti S, Van Allen E, Shukla S, Henske E, Choueiri T, Braun D. Cellular and molecular determinants of limited anti-tumor immunity in chromophobe renal carcinoma (ChRCC). Journal Of Clinical Oncology 2024, 42: 476-476. DOI: 10.1200/jco.2024.42.4_suppl.476.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsAnti-tumor immunityCell of originScRNA-seq dataPutative cell of originHLA class I genesCD8+Class I genesPD-1T cellsI geneSingle-cell T-cell receptorPoor responseResponse to immune checkpoint inhibitorsExpression of HLA class I genesInfiltration of CD8+Infiltration of T cellsCD4+ T cellsDegree of clonal expansionDownregulation of antigen presentationProportion of CD8+T cell clonotypesChromophobe renal carcinomaMolecular determinantsProtein processing pathwayAdvanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Serzan M, Jegede O, Bilen M, Braun D, Einstein D, Haas N, Hammers H, King J, Runcie K, Sosman J, Sternberg C, Yang Y, Choueiri T, Signoretti S, Atkins M. Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587). Journal Of Clinical Oncology 2024, 42: tps492-tps492. DOI: 10.1200/jco.2024.42.4_suppl.tps492.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsArm BArm APrimary endpointRate of immune-related adverse eventsMetastatic clear cell renal cell carcinomaImmune-related adverse eventsMolecular predictors of responseVEGF receptor tyrosine kinase inhibitorReceptor tyrosine kinase inhibitorsEnhance T cell primingOne-sided significance levelClear cell renal cell carcinomaAnti-PD1 inhibitorsIMDC risk groupsTreatment free intervalProgression-free survivalT cell primingTreatment-free survivalCell renal cell carcinomaSubpopulations of TregsFirst-line treatmentRenal cell carcinomaPredictors of responseAnti-tumor activityImmune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model
Wang Y, Cho J, Kastrunes G, Buck A, Razimbaud C, Culhane A, Sun J, Braun D, Choueiri T, Wu C, Jones K, Nguyen Q, Zhu Z, Wei K, Zhu Q, Signoretti S, Freeman G, Hemberg M, Marasco W. Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model. IScience 2024, 27: 108879. PMID: 38327771, PMCID: PMC10847687, DOI: 10.1016/j.isci.2024.108879.Peer-Reviewed Original ResearchCAR-T cellsChimeric antigen receptorClear cell renal cell carcinomaHematopoietic stem cellsHuman leukocyte antigenTumor microenvironmentCarbonic anhydrase IXExhausted CD8<sup>+</sup> T cellsAnti-PD-L1 monoclonal antibodyCD34<sup>+</sup> hematopoietic stem cellsMouse modelCD8<sup>+</sup> T cellsEngineered CAR-T cellsTreatment of solid tumorsReversing ITMUnfavorable tumor microenvironmentImmunosuppressive tumor microenvironmentCell renal cell carcinomaOrthotopic mouse modelRenal cell carcinomaHuman clear cell renal cell carcinomaAntitumor immunityCAR-TCell carcinomaLeukocyte antigenPD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients.
Denize T, Jegede O, Matar S, El Ahmar N, West D, Walton E, Bagheri A, Savla V, Nabil Laimon Y, Gupta S, Vemula S, Braun D, Burke K, Catalano P, Freeman G, Motzer R, Atkins M, McDermott D, Sharpe A, Choueiri T, Signoretti S. PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients. Clinical Cancer Research 2024, 30: 803-813. PMID: 38060202, PMCID: PMC10922154, DOI: 10.1158/1078-0432.ccr-23-2274.Peer-Reviewed Original ResearchPD-1 expressionObjective response rateProgression-free survivalLow objective response rateShorter progression-free survivalPD-1 blockadeRegulatory T cellsShorter overall survivalOverall survivalPD-1Nivolumab armT cellsMetastatic clear-cell renal cell carcinoma patientsMetastatic clear cell renal cell carcinomaAnti-PD-1 therapyIntratumoral regulatory T cellsClear cell renal cell carcinoma patientsRenal cell carcinoma patientsClear cell renal cell carcinomaPD-1 inhibitorsPD-1 inhibitionCell carcinoma patientsCell renal cell carcinomaExpression of CD8Tumor-infiltrating Tregs