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 modelClinical Implications of Basic Research: Exploring the Transformative Potential of Spatial 'Omics in Uro-oncology
Figiel S, Bates A, Braun D, Eapen R, Eckstein M, Manley B, Milowsky M, Mitchell T, Bryant R, Sfakianos J, Lamb A. Clinical Implications of Basic Research: Exploring the Transformative Potential of Spatial 'Omics in Uro-oncology. European Urology 2024 PMID: 39227262, DOI: 10.1016/j.eururo.2024.08.025.Peer-Reviewed Original ResearchComputational analysis workflowMolecular dataTreatment of urological cancersGenetic changesHarmonisation of protocolsMolecular technologiesPersonalised cancer therapyCellular variationDisease developmentSpatial omicsTumor microenvironmentRisk stratificationUrological cancersCancer developmentAnalysis workflowPrecision medicineIndividual malignanciesReagent costsCancer therapyUro-oncologyCancer tissuesTumorTissue architectureClinical implicationsCancerDevelopment 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 carcinomaInvestigation 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 therapyImmune-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 antigen
2023
Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases
Schoenfeld D, Moutafi M, Martinez S, Djureinovic D, Merkin R, Adeniran A, Braun D, Signoretti S, Choueiri T, Parisi F, Hurwitz M, Rimm D, Wei W, Jilaveanu L, Kluger H. Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases. Journal For ImmunoTherapy Of Cancer 2023, 11: e007240. PMID: 37586773, PMCID: PMC10432651, DOI: 10.1136/jitc-2023-007240.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaBrain metastasesPrimary tumorTumor microenvironmentDigital spatial profilingCell carcinomaActivation protein expressionInflammatory macrophage markersRCC brain metastasesInnate immune activatorsNormal kidney samplesProgressive stagesExtracranial metastasesTim-3Immune checkpointsImmune dysfunctionImmune activationRCC metastasisLonger survivalImmune activatorsMacrophage markersTreatment responseSeparate cohortTissue microarrayMetastatic samplesLeveraging 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 microenvironment
2022
Landscape 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 microenvironment