2024
CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors
Skoulidis F, Araujo H, Do M, Qian Y, Sun X, Cobo A, Le J, Montesion M, Palmer R, Jahchan N, Juan J, Min C, Yu Y, Pan X, Arbour K, Vokes N, Schmidt S, Molkentine D, Owen D, Memmott R, Patil P, Marmarelis M, Awad M, Murray J, Hellyer J, Gainor J, Dimou A, Bestvina C, Shu C, Riess J, Blakely C, Pecot C, Mezquita L, Tabbó F, Scheffler M, Digumarthy S, Mooradian M, Sacher A, Lau S, Saltos A, Rotow J, Johnson R, Liu C, Stewart T, Goldberg S, Killam J, Walther Z, Schalper K, Davies K, Woodcock M, Anagnostou V, Marrone K, Forde P, Ricciuti B, Venkatraman D, Van Allen E, Cummings A, Goldman J, Shaish H, Kier M, Katz S, Aggarwal C, Ni Y, Azok J, Segal J, Ritterhouse L, Neal J, Lacroix L, Elamin Y, Negrao M, Le X, Lam V, Lewis W, Kemp H, Carter B, Roth J, Swisher S, Lee R, Zhou T, Poteete A, Kong Y, Takehara T, Paula A, Parra Cuentas E, Behrens C, Wistuba I, Zhang J, Blumenschein G, Gay C, Byers L, Gibbons D, Tsao A, Lee J, Bivona T, Camidge D, Gray J, Lieghl N, Levy B, Brahmer J, Garassino M, Gandara D, Garon E, Rizvi N, Scagliotti G, Wolf J, Planchard D, Besse B, Herbst R, Wakelee H, Pennell N, Shaw A, Jänne P, Carbone D, Hellmann M, Rudin C, Albacker L, Mann H, Zhu Z, Lai Z, Stewart R, Peters S, Johnson M, Wong K, Huang A, Winslow M, Rosen M, Winters I, Papadimitrakopoulou V, Cascone T, Jewsbury P, Heymach J. CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors. Nature 2024, 1-10. PMID: 39385035, DOI: 10.1038/s41586-024-07943-7.Peer-Reviewed Original ResearchNon-small-cell lung cancerImmune checkpoint blockadeTumor suppressor genePD-L1Advanced non-small-cell lung cancerCD8+ cytotoxic T cellsSuppressor geneCD4+ effector cellsDual immune checkpoint blockadeMouse modelPD-L1 inhibitor durvalumabSuppressive myeloid cellsPD-L1 inhibitorsImmune-related toxicitiesPD-(L)1 inhibitorsAnti-tumor efficacyCytotoxic T cellsMyeloid cell compartmentAdverse tumor microenvironmentAssociated with higher ratesAnti-tumor activityLoss of Keap1CTLA4 inhibitorsSTK11 alterationsCheckpoint blockadeBCAM (basal cell adhesion molecule) protein expression in different tumor populations
Burela S, He M, Trontzas I, Gavrielatou N, Schalper K, Langermann S, Flies D, Rimm D, Aung T. BCAM (basal cell adhesion molecule) protein expression in different tumor populations. Discover Oncology 2024, 15: 381. PMID: 39207605, PMCID: PMC11362396, DOI: 10.1007/s12672-024-01244-1.Peer-Reviewed Original ResearchPD-L1 expressionBasal cell adhesion moleculePD-L1Quantitative immunofluorescenceAssociated with better OSPD-L1 protein expressionCancer typesBladder urothelial tumorsProtein expressionMultiple immune checkpointsHead and neckMultiple tumor typesEvidence of hypermethylationImmune checkpointsImmunotherapy responseCell adhesion moleculesTumor typesValidation cohortTumor populationCancer patientsTumorPredictive valueAdhesion moleculesNovel biomarkersWidespread expression
2023
Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy
Martinez-Morilla S, Moutafi M, Fernandez A, Jessel S, Divakar P, Wong P, Garcia-Milian R, Schalper K, Kluger H, Rimm D. Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy. OncoImmunology 2023, 12: 2260618. PMID: 37781235, PMCID: PMC10540659, DOI: 10.1080/2162402x.2023.2260618.Peer-Reviewed Original ResearchConceptsDigital spatial profilingImmune checkpoint inhibitor therapyShorter progression-free survivalQuantitative immunofluorescenceCheckpoint inhibitor therapyProgression-free survivalMetastatic melanoma patientsPre-treatment specimensIndependent validation cohortMetastatic melanoma casesAdjuvant settingNanoString GeoMxMultivariable adjustmentAdverse eventsImmunotherapy cohortInhibitor therapyPD-L1Immune markersMelanoma patientsUnivariable analysisValidation cohortImmune cellsMelanoma casesMultiplex immunofluorescenceCD95 expression
2022
Density patterns of tumor-infiltrating lymphocytes and association with objective response to nivolumab in patients with lung adenocarcinoma from CheckMate 057.
Corredor G, Ding R, Prasanna P, Barrera C, Toro P, Viswanathan V, Zens P, Berezowska S, Baxi V, Balli D, Belete M, Velcheti V, Schalper K, Madabhushi A. Density patterns of tumor-infiltrating lymphocytes and association with objective response to nivolumab in patients with lung adenocarcinoma from CheckMate 057. Journal Of Clinical Oncology 2022, 40: 2662-2662. DOI: 10.1200/jco.2022.40.16_suppl.2662.Peer-Reviewed Original ResearchTumor-infiltrating lymphocytesImmune checkpoint inhibitorsOverall survivalLung adenocarcinomaCheckMate 057Objective responseRisk scoreAnalysis of TILAdvanced-stage lung adenocarcinomaPlatinum-based chemotherapyRisk of progressionCox regression modelDeath risk scoreStage lung adenocarcinomaLung cancer subjectsRECIST v1.1Checkpoint inhibitorsHazard ratioTIL densityPD-L1Better prognosisTumor responseClinical trialsCancer subjectsNivolumab
2018
Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non–Small Cell Lung Cancer
Villarroel-Espindola F, Yu X, Datar I, Mani N, Sanmamed M, Velcheti V, Syrigos K, Toki M, Zhao H, Chen L, Herbst RS, Schalper KA. Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non–Small Cell Lung Cancer. Clinical Cancer Research 2018, 24: 1562-1573. PMID: 29203588, PMCID: PMC5884702, DOI: 10.1158/1078-0432.ccr-17-2542.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntigens, CDAntigens, Differentiation, MyelomonocyticB7 AntigensB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungCD8-Positive T-LymphocytesEvaluation Studies as TopicFemaleGene Expression Regulation, NeoplasticHumansImmunologic FactorsImmunotherapyLung NeoplasmsMaleMembrane ProteinsMutationProgrammed Cell Death 1 ReceptorRetrospective StudiesConceptsNon-small cell lung cancerHuman non-small cell lung cancerT helper cellsCytotoxic T cellsT cellsPD-1Localized expression patternQuantitative immunofluorescenceTumor-infiltrating lymphocytesCell lung cancerLung cancer casesGenomic analysisTissue microarray formatTumor-associated macrophagesPD-L1 proteinCytoplasmic staining patternClin Cancer ResExpression patternsLow mutational burdenTumor epithelial cellsSpecific genomic alterationsVISTA expressionVISTA proteinPD-L1Immunomodulatory role
2017
B7-H3 Expression in NSCLC and Its Association with B7-H4, PD-L1 and Tumor-Infiltrating Lymphocytes
Altan M, Pelekanou V, Schalper KA, Toki M, Gaule P, Syrigos K, Herbst RS, Rimm DL. B7-H3 Expression in NSCLC and Its Association with B7-H4, PD-L1 and Tumor-Infiltrating Lymphocytes. Clinical Cancer Research 2017, 23: 5202-5209. PMID: 28539467, PMCID: PMC5581684, DOI: 10.1158/1078-0432.ccr-16-3107.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedB7 AntigensB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungCell Line, TumorDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticHumansImmunohistochemistryLymphocytes, Tumor-InfiltratingMaleMiddle AgedPrognosisV-Set Domain-Containing T-Cell Activation Inhibitor 1ConceptsNon-small cell lung cancerTumor-infiltrating lymphocytesB7-H3 proteinB7-H4PD-L1B7-H3Majority of NSCLCQuantitative immunofluorescenceImmune checkpoints PD-1Major clinicopathologic variablesLevels of CD3Negative prognostic impactCell lung cancerPoor overall survivalSuccessful therapeutic targetsB7 family membersClin Cancer ResB7-H1NSCLC cohortOverall survivalPrognostic impactSmoking historyClinicopathologic characteristicsPD-1Clinical stageDifferential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer
Schalper KA, Carvajal-Hausdorf D, McLaughlin J, Altan M, Velcheti V, Gaule P, Sanmamed MF, Chen L, Herbst RS, Rimm DL. Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer. Clinical Cancer Research 2017, 23: 370-378. PMID: 27440266, PMCID: PMC6350535, DOI: 10.1158/1078-0432.ccr-16-0150.Peer-Reviewed Original ResearchMeSH KeywordsA549 CellsAgedB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungDisease-Free SurvivalDrug Resistance, NeoplasmGene Expression Regulation, NeoplasticHumansIndoleamine-Pyrrole 2,3,-DioxygenaseInterferon-gammaInterleukin-10Lymphocytes, Tumor-InfiltratingMiddle AgedNeoplasm StagingRNA, MessengerV-Set Domain-Containing T-Cell Activation Inhibitor 1ConceptsNon-small cell lung cancerB7-H4PD-L1IDO-1Lung cancerLung carcinomaQuantitative immunofluorescenceIFNγ stimulationElevated PD-L1Major clinicopathologic variablesMultiplexed quantitative immunofluorescenceOptimal clinical trialsT-cell infiltratesCell lung cancerImmune evasion pathwaysHuman lung carcinomaLung adenocarcinoma A549Cancer Genome AtlasClinicopathologic variablesMarker levelsClinical trialsStage ITherapeutic resistanceTCGA datasetA549 cellsP2.01-046 Quantitative Measurement of B7-H3 Protein Expression and Its Association with B7-H4, PD-L1 and TILs in NSCLC Topic: Immune Mechanisms in Thoracic Cancer and Targeted Therapy
Altan M, Pelekanou V, Schalper K, Toki M, Herbst R, Rimm D. P2.01-046 Quantitative Measurement of B7-H3 Protein Expression and Its Association with B7-H4, PD-L1 and TILs in NSCLC Topic: Immune Mechanisms in Thoracic Cancer and Targeted Therapy. Journal Of Thoracic Oncology 2017, 12: s813-s814. DOI: 10.1016/j.jtho.2016.11.1098.Peer-Reviewed Original Research
2016
Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer
Rehman JA, Han G, Carvajal-Hausdorf DE, Wasserman BE, Pelekanou V, Mani NL, McLaughlin J, Schalper KA, Rimm DL. Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer. Modern Pathology 2016, 30: 340-349. PMID: 27834350, PMCID: PMC5334264, DOI: 10.1038/modpathol.2016.186.Peer-Reviewed Original ResearchConceptsPD-L1 expressionPD-L1Immune cellsImmune cell PD-L1 expressionNon-small cell lung cancerNon-small cell lung cancer (NSCLC) casesCell lung cancer casesTumor cellsPD-L1 assessmentStromal immune cellsPD-L1 positivityCell lung cancerLung cancer patientsLung cancer casesRepresentative tumor areasPathologist scoresLikelihood of responseConcordance correlation coefficientRabbit monoclonal antibodyIntraclass correlation coefficientCancer patientsLung cancerImmunohistochemistry slidesCancer casesTumor tissueQuantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung Cancer
McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelakanou V, Rehman J, Velcheti V, Herbst R, LoRusso P, Rimm DL. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung Cancer. JAMA Oncology 2016, 2: 1-9. PMID: 26562159, PMCID: PMC4941982, DOI: 10.1001/jamaoncol.2015.3638.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntibodies, MonoclonalAntibody SpecificityB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungFemaleFluorescent Antibody TechniqueHumansImmunohistochemistryLung NeoplasmsMaleObserver VariationPredictive Value of TestsReproducibility of ResultsRetrospective StudiesTissue Array AnalysisConceptsTumor-infiltrating lymphocytesPD-L1 expressionPD-L1 antibodiesPD-L1 protein expressionCell lung cancerPD-L1Whole tissue sectionsQuantitative immunofluorescenceLung cancerChromogenic immunohistochemistryPoor concordanceDifferent PD-L1 antibodiesHigh tumor-infiltrating lymphocytesTumor PD-L1 expressionPD-L1 protein levelsCell lung cancer biopsiesMonoclonal antibodiesCurrent consensus guidelinesProtein expressionDurable clinical responsesMain outcome measuresEarly phase trialsLung cancer biopsiesRabbit monoclonal antibodyCorresponding tissue microarrays
2015
PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer
Wimberly H, Brown JR, Schalper K, Haack H, Silver MR, Nixon C, Bossuyt V, Pusztai L, Lannin DR, Rimm DL. PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Immunology Research 2015, 3: 326-332. PMID: 25527356, PMCID: PMC4390454, DOI: 10.1158/2326-6066.cir-14-0133.Peer-Reviewed Original ResearchConceptsTumor-infiltrating lymphocytesPD-L1 expressionPathologic complete responseNeoadjuvant chemotherapyPD-L1Breast cancerDeath 1 ligand 1PD-L1 protein expressionYale-New Haven HospitalHigh PD-L1Antitumor immune activitySubset of patientsTriple-negative patientsBreast cancer patientsTriple-negative statusImmune checkpoint proteinsImmune regulatory moleculesNew Haven HospitalSignificant multivariate modelRabbit monoclonal antibodyTILs correlateComplete responseImmune therapyCancer patientsImmune activity
2014
Programmed death-1/programmed death-1 ligand axis as a therapeutic target in oncology: current insights
Velcheti V, Schalper K, Venur V. Programmed death-1/programmed death-1 ligand axis as a therapeutic target in oncology: current insights. Journal Of Receptor Ligand And Channel Research 2014, Volume 8: 1-7. DOI: 10.2147/jrlcr.s39986.Peer-Reviewed Original ResearchPD-1Tumor typesImmune checkpoint inhibitorsDeath-1 (PD-1) pathwayPD-1 ligandsDeath-1/Death 1 ligandDurable antitumor activityImmune checkpoint pathwaysAntigen-presenting cellsPromising anticancer therapeutic strategyPD-L1Immune toleranceInvestigational agentsImmune microenvironmentClinical activityT cellsAnticancer therapeutic strategiesTherapeutic strategiesTherapeutic targetClinical developmentTumor cellsMonoclonal antibodiesAntitumor activityTherapeutic antibodiesPD-L1 expression and tumor-infiltrating lymphocytes
Schalper KA. PD-L1 expression and tumor-infiltrating lymphocytes. OncoImmunology 2014, 3: e29288. PMID: 25083339, PMCID: PMC4106164, DOI: 10.4161/onci.29288.Peer-Reviewed Original Research
2013
Programmed death ligand-1 expression in non-small cell lung cancer
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL. Programmed death ligand-1 expression in non-small cell lung cancer. Laboratory Investigation 2013, 94: 107-116. PMID: 24217091, PMCID: PMC6125250, DOI: 10.1038/labinvest.2013.130.Peer-Reviewed Original ResearchMeSH KeywordsAgedB7-H1 AntigenBiomarkers, TumorCarcinoma, Non-Small-Cell LungCell Line, TumorChi-Square DistributionCohort StudiesConnecticutFemaleGreeceHumansImmunohistochemistryLung NeoplasmsLymphocytes, Tumor-InfiltratingMalePrognosisReproducibility of ResultsRNA, MessengerSurvival AnalysisTissue Array AnalysisConceptsNon-small cell lung cancerPD-L1 expressionCell lung cancerPD-L1Tissue microarrayBetter outcomesNSCLC casesLung cancerDeath ligand 1 (PD-L1) expressionCell death ligand 1PD-L1 protein expressionEarly phase clinical trialsLigand 1 expressionTumor-infiltrating lymphocytesDeath ligand 1Significant better outcomePD-L1 mRNAPD-L1 proteinPhase clinical trialsNormal human placentaPrediction of responseQuantitative fluorescence approachesFrequency of expressionPD-1Prognostic valueSarcomatoid Lung Carcinomas Show High Levels of Programmed Death Ligand-1 (PD-L1)
Velcheti V, Rimm DL, Schalper KA. Sarcomatoid Lung Carcinomas Show High Levels of Programmed Death Ligand-1 (PD-L1). Journal Of Thoracic Oncology 2013, 8: 803-805. PMID: 23676558, PMCID: PMC3703468, DOI: 10.1097/jto.0b013e318292be18.Peer-Reviewed Original ResearchConceptsDeath ligand 1Sarcomatoid carcinomaCell lung carcinomaLung carcinomaPD-L1PD-1/PD-L1 axisPD-1/PD-L1 pathwayProgrammed Death Ligand 1PD-L1 protein expressionEffector immune responsesPD-L1 axisPD-L1 pathwayLung sarcomatoid carcinomaLung cancer cohortSarcomatoid lung carcinomasLigand 1Mouse monoclonal antibodyDeath-1Lymphocytic infiltrationRare subtypeSuch therapyCancer cohortT cellsCarcinomaTumor types