2024
TIGIT 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 microarrayGP100 expression is variable in intensity in melanoma
Mann J, Hasson N, Su D, Adeniran A, Smalley K, Djureinovic D, Jilaveanu L, Schoenfeld D, Kluger H. GP100 expression is variable in intensity in melanoma. Cancer Immunology, Immunotherapy 2024, 73: 191. PMID: 39105816, PMCID: PMC11303354, DOI: 10.1007/s00262-024-03776-5.Peer-Reviewed Original ResearchConceptsGp100 expressionCutaneous melanomaTreatment of cutaneous melanomaAdvanced cutaneous melanomaT-cell engagersImprove patient selectionMetastatic melanomaUveal melanomaMetastatic samplesPatient selectionClinical trialsMelanomaQuantitative immunofluorescence methodGp100Improve outcomesImmunofluorescence methodTherapeutic intentDrugCellular productsExpressionTebentafuspImmunohistochemistryMelanocortin-1 Receptor Expression as a Marker of Progression in Melanoma
Su D, Djureinovic D, Schoenfeld D, Marquez-Nostra B, Olino K, Jilaveanu L, Kluger H. Melanocortin-1 Receptor Expression as a Marker of Progression in Melanoma. JCO Precision Oncology 2024, 8: e2300702. PMID: 38662983, PMCID: PMC11513442, DOI: 10.1200/po.23.00702.Peer-Reviewed Original ResearchConceptsMC1R expressionMelanoma progressionAssociated with shorter survivalStages of melanoma progressionCases of benign neviChronic sun exposureMarkers of progressionHuman melanoma tissuesBreslow thicknessMelanocortin-1Metastatic melanomaOverall survivalPrimary melanomaMetastatic tumorsMelanoma cohortReceptor expressionPredictive biomarkersAggressive melanomaPrimary lesionTissue microarrayShorter survivalMale sexQuantitative immunofluorescenceBenign neviClinical trialsDigital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma
Su D, Schoenfeld D, Ibrahim W, Cabrejo R, Djureinovic D, Baumann R, Rimm D, Khan S, Halaban R, Kluger H, Olino K, Galan A, Clune J. Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma. Journal For ImmunoTherapy Of Cancer 2024, 12: e008646. PMID: 38519058, PMCID: PMC10961546, DOI: 10.1136/jitc-2023-008646.Peer-Reviewed Original ResearchConceptsCTLA-4 expression levelsCancer-associated fibroblastsAssociated with worse survivalExpression of immune checkpointsLAG-3 expressionDesmoplastic melanomaLymphoid aggregatesCTLA-4PD-1Immune checkpointsIntratumoral leukocytesLAG-3Tumor compartmentsWorse survivalCD20+B cellsIncreased expression of immune checkpointsProgrammed cell death protein 1Macrophage/monocyte markerSentinel lymph node positivityCell death protein 1Associated with poor prognosisLymph node positivityDense fibrous stromaPotential prognostic significanceCore of tumorsUpdate on Biomarkers in Renal Cell Carcinoma.
Saliby R, Saad E, Kashima S, Schoenfeld D, Braun D. Update on Biomarkers in Renal Cell Carcinoma. American Society Of Clinical Oncology Educational Book 2024, 44: e430734. PMID: 38207251, DOI: 10.1200/edbk_430734.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsRenal cell carcinomaCell carcinomaMetastatic renal cell carcinomaTumor intrinsic featuresImmune checkpoint inhibitorsRobust predictive biomarkersCheckpoint inhibitorsDurable responsesOverall survivalCare regimensPathological characteristicsPredictive biomarkersTherapeutic responseTreatment paradigmImmune systemHost factorsTranscriptional signatureGenomic alterationsTumor heterogeneityBiomarkersCarcinomaBiomarker discoveryInnovative technological approachesRegimens
2023
A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better
Djureinovic D, Weiss S, Krykbaeva I, Qu R, Vathiotis I, Moutafi M, Zhang L, Perdigoto A, Wei W, Anderson G, Damsky W, Hurwitz M, Johnson B, Schoenfeld D, Mahajan A, Hsu F, Miller-Jensen K, Kluger Y, Sznol M, Kaech S, Bosenberg M, Jilaveanu L, Kluger H. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better. Molecular Cancer 2023, 22: 182. PMID: 37964379, PMCID: PMC10644655, DOI: 10.1186/s12943-023-01884-x.Peer-Reviewed Original ResearchConceptsStable diseasePartial responseMacrophage populationsThree-drug regimenUnconfirmed partial responsePhase I trialLimited treatment optionsMonocyte/macrophage populationNon-classical monocytesMurine melanoma modelTreatment-related changesResultsThirteen patientsWorse survivalI trialInflammatory tumorPatient populationTreatment optionsImmune cellsDisease progressionMurine studiesPreclinical modelsResistant melanomaAntigen presentationMurine modelCyTOF analysisImmune 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 samplesResponse to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng
Aizenbud L, Schoenfeld D, Caulfield J, Mann J, Austin M, Perdigoto A, Herold K, Kluger H. Response to "NLRC5 germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng. Journal For ImmunoTherapy Of Cancer 2023, 11: e007397. PMID: 37349129, PMCID: PMC10314693, DOI: 10.1136/jitc-2023-007397.Peer-Reviewed Original ResearchLenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments anti-tumor activity in melanoma
Tran T, Caulfield J, Zhang L, Schoenfeld D, Djureinovic D, Chiang V, Oria V, Weiss S, Olino K, Jilaveanu L, Kluger H. Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments anti-tumor activity in melanoma. JCI Insight 2023, 8: e157347. PMID: 36821392, PMCID: PMC10132152, DOI: 10.1172/jci.insight.157347.Peer-Reviewed Original ResearchConceptsTumor microenvironmentAnti-VEGFCytokine/chemokine signalingCytokine/chemokine profilingBlood-brain barrier modelBlood vesselsLeukocyte transmigrationTumor-associated blood vesselsTumor-associated macrophagesIntratumoral blood vesselsAnti-angiogenesis effectAnti-tumor activityExtracranial diseasePlasmacytoid DCsImmune checkpointsPD-1Melanoma murine modelImmune infiltrationBBB modelChemokine profilingEndothelial stabilizationMurine modelLenvatinibCombined targetingMelanoma modelOutcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma
Dizman N, Austin M, Considine B, Jessel S, Schoenfeld D, Merl M, Hurwitz M, Sznol M, Kluger H. Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma. Clinical Genitourinary Cancer 2023, 21: 221-229. PMID: 36681606, DOI: 10.1016/j.clgc.2023.01.002.Peer-Reviewed Original ResearchConceptsMetastatic renal cell carcinomaPembrolizumab/axitinibObjective response rateProgression-free survivalImmune checkpoint inhibitorsMedian progression-free survivalAdverse eventsRenal cell carcinomaCell carcinomaClear cell metastatic renal cell carcinomaVascular endothelial growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsCombination immune checkpoint inhibitorsGrade 5 adverse eventsPrior immune checkpoint inhibitorsSuperior progression-free survivalReceptor tyrosine kinase inhibitorsYale-New Haven HospitalFurther-line treatmentNivolumab/ipilimumabRECIST 1.1 criteriaResponse-evaluable patientsDisease control rateSecond-line therapyFirst-line treatment
2022
Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance
Schoenfeld D, Merkin R, Moutafi M, Martinez S, Adeniran A, Kumar D, Jilaveanu L, Hurwitz M, Rimm D, Kluger H. Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance. Frontiers In Oncology 2022, 12: 990367. PMID: 36313654, PMCID: PMC9608089, DOI: 10.3389/fonc.2022.990367.Peer-Reviewed Original ResearchRenal cell carcinomaImmune checkpoint inhibitorsMetastatic sitesBrain metastasesPrimary tumorMechanisms of resistancePD-1/PD-L1Anti-PD-1 therapyHigh-risk clinical characteristicsLarger primary tumor sizeAdvanced renal cell carcinomaAlternative immune checkpointsCertain drug regimensPoor-risk diseasePD-1 inhibitorsMinority of patientsPrimary tumor sizeLonger overall survivalGrade 4 tumorsProtein levelsPrimary RCC tumorsAttractive therapeutic targetIdentification of subgroupsCheckpoint inhibitorsUpfront therapyLoss of PBRM1 alters promoter histone modifications and activates ALDH1A1 to drive renal cell carcinomaPBRM1 loss increases H3K4me3 marks and expression of ALDH1A1
Schoenfeld D, Zhou R, Zairis S, Su W, Steinbach N, Mathur D, Bansal A, Zachem A, Tavarez B, Hasson D, Bernstein E, Rabadan R, Parsons R. Loss of PBRM1 alters promoter histone modifications and activates ALDH1A1 to drive renal cell carcinomaPBRM1 loss increases H3K4me3 marks and expression of ALDH1A1. Molecular Cancer Research 2022, 20: 1193-1207. PMID: 35412614, PMCID: PMC9357026, DOI: 10.1158/1541-7786.mcr-21-1039.Peer-Reviewed Original ResearchConceptsRetinoic acid biosynthesisSuch target genesPromoter histone modificationsAcid biosynthesisHistone modificationsClear cell renal cell carcinomaTarget genesLoss of PBRM1SWI/SNF complexSWI/SNF chromatinSWI/SNF subunitsHistone modification ChIP-seqSWI/SNF componentsATAC-seq dataCcRCC cell linesDe novo gainPBAF subunitsH3K4me3 peaksH3K4me3 marksPBAF complexSNF complexEpigenomic approachesChIP-seqRNA-seqHigh mutation frequency
2015
PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion
Mense SM, Barrows D, Hodakoski C, Steinbach N, Schoenfeld D, Su W, Hopkins BD, Su T, Fine B, Hibshoosh H, Parsons R. PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion. Science Signaling 2015, 8: ra32. PMID: 25829446, PMCID: PMC4874664, DOI: 10.1126/scisignal.2005840.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell MovementDNA PrimersFluorescent Antibody TechniqueGene Knockout TechniquesGenetic VectorsGuanine Nucleotide Exchange FactorsHumansImmunoblottingImmunoprecipitationLentivirusMiceNeoplasm InvasivenessPolymerase Chain ReactionPTEN PhosphohydrolaseRac1 GTP-Binding ProteinRNA, Small InterferingStatistics, NonparametricConceptsLipid phosphatase activityPTEN-mediated inhibitionGEF activityCancer mutantsCell migrationNucleotide exchange assaysPhosphatase activityTumor suppressor PTENMouse embryonic fibroblastsTumor cell invasionPI3K pathwayHuman tumor dataKinase AktSuppressor PTENTail domainEmbryonic fibroblastsGTPase Rac1PREX2 mutationsImmortalized melanocytesMutantsCell invasionHigh PTEN expressionK pathwayRac1Breast cancer cell lines
2012
Expression of the p53 Target CDIP Correlates with Sensitivity to TNFα-Induced Apoptosis in Cancer Cells
Brown-Endres L, Schoenfeld D, Tian F, Kim HG, Namba T, Muñoz-Fontela C, Mandinova A, Aaronson SA, Lee SW. Expression of the p53 Target CDIP Correlates with Sensitivity to TNFα-Induced Apoptosis in Cancer Cells. Cancer Research 2012, 72: 2373-2382. PMID: 22549949, PMCID: PMC3349239, DOI: 10.1158/0008-5472.can-11-3369.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisApoptosis Regulatory ProteinsCell Line, TumorFemaleGene Expression Regulation, NeoplasticHumansInterleukin-8MAP Kinase Kinase 4MAP Kinase Signaling SystemMiceMice, NudeNF-kappa BReactive Oxygen SpeciesRecombinant ProteinsTumor Necrosis Factor-alphaTumor Suppressor Protein p53ConceptsApoptotic cell fateCell fateCancer cellsP53-mediated deathGenotoxic stressAntiapoptotic programGrowth-suppressive effectsJNK activationApoptotic pathwaySurvival responseApoptosisDual roleExpression correlatesCellsCDIPPathwayPleiotropic cytokineFateExpressionPredictive biomarkersTNFαRegulatorDeathSurvivalActivation
2006
PECAM-1 Affects GSK-3β-Mediated β-Catenin Phosphorylation and Degradation
Biswas P, Canosa S, Schoenfeld D, Schoenfeld J, Li P, Cheas LC, Zhang J, Cordova A, Sumpio B, Madri JA. PECAM-1 Affects GSK-3β-Mediated β-Catenin Phosphorylation and Degradation. American Journal Of Pathology 2006, 169: 314-324. PMID: 16816383, PMCID: PMC1698776, DOI: 10.2353/ajpath.2006.051112.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBeta CateninBlotting, WesternCapillary PermeabilityCells, CulturedEndothelial CellsFluorescent Antibody TechniqueGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHistamineHistamine AgentsHumansMiceModels, BiologicalPhosphatidylinositol 3-KinasesPhosphorylationPlatelet Endothelial Cell Adhesion Molecule-1Proto-Oncogene Proteins c-aktReceptors, HistamineSignal TransductionConceptsAdherens junctionsSerine phosphorylationSrc homology 2 domainBeta-catenin expression levelsAdherens junction componentsSerine phosphorylation levelEndothelial cellsΒ-catenin phosphorylationPECAM-1Cell biological responsesCytoplasmic domainSHP-2Proteosomal degradationGSK-3betaDynamic regulatorJunction componentsPhosphorylation levelsPhosphorylationEndothelial cell adhesion molecule-1Expression levelsGSK-3βBiological responsesEndothelial barrier permeabilityMice exhibitCell adhesion molecule-1
2005
Identification of the regions of PECAM-1 involved in β- and γ-catenin associations
Biswas P, Zhang J, Schoenfeld JD, Schoenfeld D, Gratzinger D, Canosa S, Madri JA. Identification of the regions of PECAM-1 involved in β- and γ-catenin associations. Biochemical And Biophysical Research Communications 2005, 329: 1225-1233. PMID: 15766557, DOI: 10.1016/j.bbrc.2005.02.095.Peer-Reviewed Original Research
2003
PECAM-1 promotes β-catenin accumulation and stimulates endothelial cell proliferation
Biswas P, Canosa S, Schoenfeld J, Schoenfeld D, Tucker A, Madri JA. PECAM-1 promotes β-catenin accumulation and stimulates endothelial cell proliferation. Biochemical And Biophysical Research Communications 2003, 303: 212-218. PMID: 12646189, DOI: 10.1016/s0006-291x(03)00313-9.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsBeta CateninBlotting, WesternCell AdhesionCell DivisionCytoplasmCytoskeletal ProteinsEndotheliumFlow CytometryHumansLungMiceMice, KnockoutMicroscopy, FluorescencePlatelet Endothelial Cell Adhesion Molecule-1Precipitin TestsSignal TransductionTrans-ActivatorsTranscription, GeneticTransfectionConceptsPECAM-1-positive endothelial cellsBeta-catenin proteinCell proliferationEndothelial cellsPECAM-1Beta-catenin localizationCytoplasmic domainΒ-catenin accumulationFull-length PECAM-1Functional consequencesEndothelial cell proliferationCell membraneKnockout animalsAdhesion moleculesLess accumulationCellsAccumulationProliferative rateProliferationMembraneProteinBinds