2024
Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma
Schoenfeld D, Djureinovic D, Su D, Zhang L, Lu B, Kamga L, Mann J, Huck J, Hurwitz M, Braun D, Jilaveanu L, Ring A, Kluger H. Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti-CTLA-4 in renal cell carcinoma. JCI Insight 2024 PMID: 39561007, DOI: 10.1172/jci.insight.184545.Peer-Reviewed Original ResearchAnti-CTLA-4Renal cell carcinomaIL-18IL-18BPCell carcinomaTumor microenvironmentTumor typesPatients treated with immune checkpoint inhibitorsRegulatory T cell levelsAnti-PD-1 treatmentCD8+ T cellsAnti-PD-1Immune checkpoint inhibitorsCell renal cell carcinomaNon-responder patientsMyeloid cell populationsT cell levelsCytokine interleukin-18Anti-cancer efficacySecreted binding proteinCheckpoint inhibitorsResponding patientsPreclinical modelsT cellsMurine modelTIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3
Perales O, Jilaveanu L, Adeniran A, Su D, Hurwitz M, Braun D, Kluger H, Schoenfeld D. TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3. Cancer Immunology, Immunotherapy 2024, 73: 192. PMID: 39105820, PMCID: PMC11303630, DOI: 10.1007/s00262-024-03773-8.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaRenal cell carcinoma tumorsT cellsTIGIT expressionCheckpoint inhibitorsPD-1Likelihood of response to therapyTumor-infiltrating T cellsCD3+ T cellsRenal cell carcinoma metastasisTreatment of renal cell carcinomaImmune checkpoint inhibitorsInfiltrating T cellsPurposeImmune checkpoint inhibitorsResponse to therapyT cell immunoglobulinCD3+ levelsMetastatic RCC specimensAdjacent normal renal tissuesNormal renal tissuesQuantitative immunofluorescence analysisCell carcinomaResistant diseasePotential therapeutic targetTissue microarrayDevelopment of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC)
Kashima S, Gupta R, Moritz V, Sadak K, Adeniran A, Humphrey P, Dinulescu D, Palmer D, Hammond S, Bosenberg M, Hurwitz M, Kenney P, Braun D. Development of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC). The Oncologist 2024, 29: s5-s6. PMCID: PMC11301923, DOI: 10.1093/oncolo/oyae181.008.Peer-Reviewed Original ResearchRCC tumor microenvironmentPatient-derived tumor modelsRenal cell carcinomaImmune checkpoint inhibitorsT cell functionPeripheral blood mononuclear cellsEnzyme-linked immunosorbent assayTumor microenvironmentT cellsFlow cytometryTumor fragmentsIFN-gTumor modelTumor samplesCytokine productionHealthy donor peripheral blood mononuclear cellsImpact of immune checkpoint inhibitorsAnti-PD-1 monoclonal antibodyDonor peripheral blood mononuclear cellsCD4+CD25+ regulatory T cellsCD8+ T cell populationsResection of renal cell carcinomaSurgical resection of renal cell carcinomaAnti-PD-1 antibodyMetastatic renal cell carcinomaEmerging 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 therapySLAMF7+ CD8+ T cells exhibit decreased anti-tumor responses in renal cell carcinoma
Wirth L, Hugaboom M, Street K, Ruthen N, Jegede O, Schindler N, McDermott D, Plimack E, Sosman J, Haas N, Hurwitz M, Hammers H, Signoretti S, Atkins M, Wu C, Braun D. SLAMF7+ CD8+ T cells exhibit decreased anti-tumor responses in renal cell carcinoma. The Journal Of Immunology 2024, 212: 1491_5876-1491_5876. DOI: 10.4049/jimmunol.212.supp.1491.5876.Peer-Reviewed Original ResearchCD8+ T cellsImmune-checkpoint inhibitorsRenal cell carcinomaCD8+ T-cell effector functionT cell effector functionT cellsCell carcinomaResistance to immune-checkpoint inhibitorsEffector functionsPopulation of CD8+ T cellsCD3+ T cellsTreatment of renal cell carcinomaHealthy human PBMCTumor-infiltrating lymphocytesAnti-tumor responsesPatient T cellsReduction of pro-inflammatory cytokinesAnti-tumor functionPro-inflammatory cytokinesSingle-cell transcriptome analysisNivolumab monotherapySLAMF7 expressionClinical benefitGranzyme BIFN-gCellular 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 pathwayPD-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
2023
Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma
Choueiri T, Donahue A, Braun D, Rini B, Powles T, Haanen J, Larkin J, Mu X, Pu J, Teresi R, di Pietro A, Robbins P, Motzer R. Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma. Cancer Discovery 2023, 14: of1-of18. PMID: 38385846, PMCID: PMC10905671, DOI: 10.1158/2159-8290.cd-23-0680.Peer-Reviewed Original ResearchProlonged progression-free survivalT cellsTreatment of advanced renal cell carcinomaImmunomodulatory mechanismsAdvanced renal cell carcinomaBaseline tumor tissuePD-L1 inhibitorsProgression-free survivalContribution of tumor biologyT cell numbersTumors harboring mutationsTumor molecular subtypeLongitudinal blood samplesRenal cell carcinomaCell-mediated mechanismsAnalysis of tumorsInnate immune subsetsJAVELIN RenalSunitinib armPD-L1Immune subsetsCell carcinomaMolecular subtypesTumor biologyTreatment regimensLeveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies
Anderson K, Braun D, Buqué A, Gitto S, Guerriero J, Horton B, Keenan B, Kim T, Overacre-Delgoffe A, Ruella M, Triplett T, Veeranki O, Verma V, Zhang F. Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies. Journal For ImmunoTherapy Of Cancer 2023, 11: e006533. PMID: 37399356, PMCID: PMC10314654, DOI: 10.1136/jitc-2022-006533.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsImmune resistance mechanismsImmune resistanceChimeric antigen receptor T cellsAntigen receptor T cellsImmune checkpoint inhibitorsReceptor T cellsVariety of malignanciesNew therapeutic strategiesResistance mechanismsCheckpoint inhibitorsDurable responsesMost patientsAnticancer immunotherapyTherapy combinationsCurrent therapiesT cellsIndividual patientsSolid cancersTherapeutic strategiesTumor profilingPatientsOverall efficacySuppressive mechanismsBispecific antibodiesTumor microenvironmentCirculating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma
Saliby R, Zarif T, Bakouny Z, Shah V, Xie W, Flippot R, Denize T, Kane M, Madsen K, Ficial M, Hirsch L, Wei X, Steinharter J, Harshman L, Vaishampayan U, Severgnini M, McDermott D, Lee G, Xu W, Van Allen E, McGregor B, Signoretti S, Choueiri T, McKay R, Braun D. Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma. Cancer Immunology Research 2023, 11: 1114-1124. PMID: 37279009, PMCID: PMC10526700, DOI: 10.1158/2326-6066.cir-22-0996.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaT cellsWorse PFSImmunotherapy responseCell carcinomaPeripheral immune cell populationsWorse progression-free survivalSarcomatoid renal cell carcinomaPhase II clinical trialImmunotherapy-based combinationsValue of tumourPoor-risk patientsProgression-free survivalImmune cell populationsVascular endothelial growth factorKidney cancer diagnosisEndothelial growth factorFuture biomarker studiesLack of responseInflammatory modulesExhausted CD8Variant histologyOverall survivalPD-L1Sarcomatoid differentiation
2022
Spatial maps of T cell receptors and transcriptomes reveal distinct immune niches and interactions in the adaptive immune response
Liu S, Iorgulescu J, Li S, Borji M, Barrera-Lopez I, Shanmugam V, Lyu H, Morriss J, Garcia Z, Murray E, Reardon D, Yoon C, Braun D, Livak K, Wu C, Chen F. Spatial maps of T cell receptors and transcriptomes reveal distinct immune niches and interactions in the adaptive immune response. Immunity 2022, 55: 1940-1952.e5. PMID: 36223726, PMCID: PMC9745674, DOI: 10.1016/j.immuni.2022.09.002.Peer-Reviewed Original ResearchConceptsImmune responseTCR repertoireAntigen-specific immune responsesCell receptorDistinct TCR repertoireAdaptive immune responsesLymphoid germinal centersRenal cell carcinomaHeterogeneous immune responseCell carcinomaImmune cellsCell clonotypesT cellsImmune nichesAdjacent tumorGerminal centersMelanoma specimensCell responsesMouse spleenDistinct gene expressionGene expressionReceptorsCharacteristic locationCell typesCellsLandscape of helper and regulatory antitumour CD4+ T cells in melanoma
Oliveira G, Stromhaug K, Cieri N, Iorgulescu J, Klaeger S, Wolff J, Rachimi S, Chea V, Krause K, Freeman S, Zhang W, Li S, Braun D, Neuberg D, Carr S, Livak K, Frederick D, Fritsch E, Wind-Rotolo M, Hacohen N, Sade-Feldman M, Yoon C, Keskin D, Ott P, Rodig S, Boland G, Wu C. Landscape of helper and regulatory antitumour CD4+ T cells in melanoma. Nature 2022, 605: 532-538. PMID: 35508657, PMCID: PMC9815755, DOI: 10.1038/s41586-022-04682-5.Peer-Reviewed Original ResearchConceptsHLA class IIT cellsClass IIHLA classImmune evasionHuman leukocyte antigen class IIMelanoma specimensClass II positivityTumor-reactive CD4T regulatory (Treg) cellsAntigen-presenting cellsTumor-associated antigensHLA class IHuman melanoma specimensRecognition of antigenAntitumour responseImmunosuppressive CD4Treg clonesTreg cellsRegulatory cellsCytotoxic CD4Neoantigen loadTumor antigensCD4Tumor microenvironmentSpatially mapping T cell receptors and transcriptomes
Liu S, Iorgulescu J, Li S, Barrera-Lopez I, Borji M, Shanmugam V, Morriss J, Garcia Z, Murray E, Braun D, Livak K, Wu C, Chen F. Spatially mapping T cell receptors and transcriptomes. The Journal Of Immunology 2022, 208: 172.01-172.01. DOI: 10.4049/jimmunol.208.supp.172.01.Peer-Reviewed Original ResearchT cell clonotypesT cell receptorCell clonotypesGerminal centersTCR repertoireT cellsAntigen-specific immune responsesHuman reactive lymph nodesDistinct TCR repertoireImmune checkpoint blockadeReactive lymph nodesRenal cell carcinomaAbstract T cellsT cell maturationT cell developmentCheckpoint blockadeLymph nodesCell carcinomaImmune microenvironmentImmune responseClonotypesMouse spleenCell maturationCell receptorReceptorsTumor-Infiltrating T Cells — A Portrait
Braun DA, Wu CJ. Tumor-Infiltrating T Cells — A Portrait. New England Journal Of Medicine 2022, 386: 992-994. PMID: 35263526, DOI: 10.1056/nejmcibr2119477.Peer-Reviewed Original Research