2024
Digital 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 tumors
2021
Interplay between copy number alterations and immune profiles in the early breast cancer Scandinavian Breast Group 2004-1 randomized phase II trial: results from a feasibility study
Zerdes I, Simonetti M, Matikas A, Harbers L, Acs B, Boyaci C, Zhang N, Salgkamis D, Agartz S, Moreno-Ruiz P, Bai Y, Rimm DL, Hartman J, Mezheyeuski A, Bergh J, Crosetto N, Foukakis T. Interplay between copy number alterations and immune profiles in the early breast cancer Scandinavian Breast Group 2004-1 randomized phase II trial: results from a feasibility study. Npj Breast Cancer 2021, 7: 144. PMID: 34799582, PMCID: PMC8604966, DOI: 10.1038/s41523-021-00352-3.Peer-Reviewed Original ResearchMultiplexed fluorescent immunohistochemistryPhase II trialII trialEarly breast cancer patientsSomatic copy number alterationsCopy number alterationsEarly breast cancerBreast cancer patientsAbundant immune cellsImmune cell compositionParaffin-embedded tissue samplesNumber alterationsImmune profilePD-1PD-L1Immune profilingLymphocytic infiltrationCancer patientsImmune cellsBreast cancerT cellsLarge cohortFluorescent immunohistochemistryTissue samplesPathological samplesMulti-institutional TSA-amplified Multiplexed Immunofluorescence Reproducibility Evaluation (MITRE) Study
Taube JM, Roman K, Engle EL, Wang C, Ballesteros-Merino C, Jensen SM, McGuire J, Jiang M, Coltharp C, Remeniuk B, Wistuba I, Locke D, Parra ER, Fox BA, Rimm DL, Hoyt C. Multi-institutional TSA-amplified Multiplexed Immunofluorescence Reproducibility Evaluation (MITRE) Study. Journal For ImmunoTherapy Of Cancer 2021, 9: e002197. PMID: 34266881, PMCID: PMC8286792, DOI: 10.1136/jitc-2020-002197.Peer-Reviewed Original ResearchConceptsPD-1/PD-L1 axisPD-L1 axisMultiplexed immunofluorescenceTumor cellsBreast carcinomaNon-small cell lung cancer (NSCLC) tissuesCell lung cancer tissuesCell density assessmentPD-L1 expressionLung cancer tissuesTissue sectionsPercent positive cellsAverage concordanceClinical laboratory processPDL1 expressionMIF assayPD-1PD-L1Predictive biomarkersLow-level expressionPositive cellsCancer tissuesFluorescent detection reagentMultisite trialChromogenic assayAnalysis of multispectral imaging with the AstroPath platform informs efficacy of PD-1 blockade
Berry S, Giraldo NA, Green BF, Cottrell TR, Stein JE, Engle EL, Xu H, Ogurtsova A, Roberts C, Wang D, Nguyen P, Zhu Q, Soto-Diaz S, Loyola J, Sander IB, Wong PF, Jessel S, Doyle J, Signer D, Wilton R, Roskes JS, Eminizer M, Park S, Sunshine JC, Jaffee EM, Baras A, De Marzo AM, Topalian SL, Kluger H, Cope L, Lipson EJ, Danilova L, Anders RA, Rimm DL, Pardoll DM, Szalay AS, Taube JM. Analysis of multispectral imaging with the AstroPath platform informs efficacy of PD-1 blockade. Science 2021, 372 PMID: 34112666, PMCID: PMC8709533, DOI: 10.1126/science.aba2609.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntigens, CDAntigens, Differentiation, MyelomonocyticAntineoplastic Agents, ImmunologicalB7-H1 AntigenBiomarkers, TumorCD8 AntigensFemaleFluorescent Antibody TechniqueForkhead Transcription FactorsHumansImmune Checkpoint ProteinsMacrophagesMaleMelanomaMiddle AgedPrognosisProgrammed Cell Death 1 ReceptorProgression-Free SurvivalReceptors, Cell SurfaceSingle-Cell AnalysisSOXE Transcription FactorsT-Lymphocyte SubsetsTreatment OutcomeTumor MicroenvironmentConceptsAnti-programmed cell death 1Anti-PD-1 blockadePD-1 blockadeCell death 1Tissue-based biomarkersLong-term survivalTumor tissue sectionsDeath-1PD-1PD-L1Immunoregulatory moleculesT cellsIndependent cohortMyeloid cellsMelanoma specimensMultiple cell typesTissue sectionsLow/BlockadeCell typesDistinct expression patternsExpression patternsImagingCD8Foxp3Quantitative immunofluorescence and mRNA analysis of immune-related biomarker groups in matched paired tumor samples from OPHELIA window study in head and neck squamous cell carcinoma (HNSCC).
Psyrri A, Moutafi M, Koliou G, Papaxoinis G, Gavrielatou N, Economopoulou P, Kotsantis I, Gkotzamanidou M, Anastasiou M, Pectasides D, Fernandez A, Yaghoobi V, Shafi S, Vathiotis I, Aung T, Gkolfinopoulos S, Foukas P, Fountzilas G, Rimm D. Quantitative immunofluorescence and mRNA analysis of immune-related biomarker groups in matched paired tumor samples from OPHELIA window study in head and neck squamous cell carcinoma (HNSCC). Journal Of Clinical Oncology 2021, 39: 6064-6064. DOI: 10.1200/jco.2021.39.15_suppl.6064.Peer-Reviewed Original ResearchCombined positive scorePD-L1 expressionQuantitative immunofluorescencePD-L1Preclinical modelsCD8 T cell infiltrationNeck squamous cell carcinomaPhase II trialReal-time quantitative reverse transcription polymerase chain reactionT cell infiltrationPD-L1 upregulationSquamous cell carcinomaPD-L1 mRNAQuantitative reverse transcription polymerase chain reactionReverse transcription-polymerase chain reactionBiomarker groupsWindow studyTranscription-polymerase chain reactionSTING protein levelsPost-treatment samplesII trialAntitumor immunityImmune infiltratesPD-1Dual blockadePD-L1 as a biomarker of response to immune-checkpoint inhibitors
Doroshow DB, Bhalla S, Beasley MB, Sholl LM, Kerr KM, Gnjatic S, Wistuba II, Rimm DL, Tsao MS, Hirsch FR. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nature Reviews Clinical Oncology 2021, 18: 345-362. PMID: 33580222, DOI: 10.1038/s41571-021-00473-5.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsSelection of patientsPD-L1L1 antibodyImmunohistochemistry assaysPD-L1 immunohistochemistry assaysOutcomes of patientsBiomarkers of responseCompanion diagnostic assayTypes of cancerPD-1Clinical outcomesSelection biomarkerProspective comparisonClinical challengeNew therapiesFuture treatmentPatientsSolid tumorsClinical useSpecific agentsInter-assay variabilityBiomarkersCurrent roleDiagnostic assays
2019
Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non–Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis
Datar I, Sanmamed MF, Wang J, Henick BS, Choi J, Badri T, Dong W, Mani N, Toki M, Mejías L, Lozano MD, Perez-Gracia JL, Velcheti V, Hellmann MD, Gainor JF, McEachern K, Jenkins D, Syrigos K, Politi K, Gettinger S, Rimm DL, Herbst RS, Melero I, Chen L, Schalper KA. Expression Analysis and Significance of PD-1, LAG-3, and TIM-3 in Human Non–Small Cell Lung Cancer Using Spatially Resolved and Multiparametric Single-Cell Analysis. Clinical Cancer Research 2019, 25: 4663-4673. PMID: 31053602, PMCID: PMC7444693, DOI: 10.1158/1078-0432.ccr-18-4142.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CDBiomarkers, TumorCarcinoma, Non-Small-Cell LungGene Expression Regulation, NeoplasticHepatitis A Virus Cellular Receptor 2HumansLung NeoplasmsLymphocyte ActivationLymphocyte Activation Gene 3 ProteinLymphocytes, Tumor-InfiltratingPrognosisProgrammed Cell Death 1 ReceptorRetrospective StudiesSingle-Cell AnalysisSurvival RateConceptsNon-small cell lung cancerHuman non-small cell lung cancerTumor-infiltrating lymphocytesAdvanced non-small cell lung cancerTim-3PD-1Cell lung cancerLAG-3Lung cancerPD-1 axis blockadeShorter progression-free survivalBaseline samplesTim-3 protein expressionMajor clinicopathologic variablesMultiplexed quantitative immunofluorescencePD-1 expressionProgression-free survivalTim-3 expressionLAG-3 expressionT-cell phenotypeTumor mutational burdenImmune inhibitory receptorsImmune evasion pathwaysTIM-3 proteinMass cytometry analysis
2018
Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement
Johnson DB, Nixon MJ, Wang Y, Wang DY, Castellanos E, Estrada MV, Ericsson-Gonzalez PI, Cote CH, Salgado R, Sanchez V, Dean PT, Opalenik SR, Schreeder DM, Rimm DL, Kim JY, Bordeaux J, Loi S, Horn L, Sanders ME, Ferrell PB, Xu Y, Sosman JA, Davis RS, Balko JM. Tumor-specific MHC-II expression drives a unique pattern of resistance to immunotherapy via LAG-3/FCRL6 engagement. JCI Insight 2018, 3: e120360. PMID: 30568030, PMCID: PMC6338319, DOI: 10.1172/jci.insight.120360.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAnimalsAntibodies, NeutralizingAntigens, CDBreast NeoplasmsCD4-Positive T-LymphocytesCell Line, TumorHistocompatibility Antigens Class IIHLA-DR AntigensHumansImmunotherapyKiller Cells, NaturalLigandsLymphocyte Activation Gene 3 ProteinMiceProgrammed Cell Death 1 ReceptorReceptors, Antigen, T-CellReceptors, Cell SurfaceT-LymphocytesTumor MicroenvironmentConceptsMHC-II expressionT cellsAnti-PD-1 therapyTumor cellsPD-1 pathwayTumor-intrinsic factorsPD-1-targeted immunotherapiesMHC-II receptorsDurable responsesPD-1Immune activationImmunotherapy targetPreclinical modelsLAG-3TumorsUnique patternMHCEnhanced expressionInhibitory functionAdaptive resistanceNovel inhibitory functionImmunotherapyPatientsContext-dependent mechanismsCells
2017
Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer
Gettinger S, Choi J, Hastings K, Truini A, Datar I, Sowell R, Wurtz A, Dong W, Cai G, Melnick MA, Du VY, Schlessinger J, Goldberg SB, Chiang A, Sanmamed MF, Melero I, Agorreta J, Montuenga LM, Lifton R, Ferrone S, Kavathas P, Rimm DL, Kaech SM, Schalper K, Herbst RS, Politi K. Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer. Cancer Discovery 2017, 7: cd-17-0593. PMID: 29025772, PMCID: PMC5718941, DOI: 10.1158/2159-8290.cd-17-0593.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsPatient-derived xenograftsHLA class ILung cancerClass ICell surface HLA class ILung cancer mouse modelPD-1 blockadeStandard treatment algorithmCancer mouse modelLung cancer samplesDefective antigen processingCheckpoint inhibitorsPD-1Treatment algorithmMouse modelAntagonistic antibodiesDiverse malignanciesAntigen processingCancer samplesB2MHomozygous lossTumorsCancerRecurrent mutationsB7-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 stagePD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors
Kluger HM, Zito CR, Turcu G, Baine M, Zhang H, Adeniran A, Sznol M, Rimm DL, Kluger Y, Chen L, Cohen JV, Jilaveanu LB. PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clinical Cancer Research 2017, 23: 4270-4279. PMID: 28223273, PMCID: PMC5540774, DOI: 10.1158/1078-0432.ccr-16-3146.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerPD-L1 expressionRenal cell carcinomaPD-1 inhibitorsCell carcinomaImmune-infiltrating cellsMelanoma patientsPD-L1Tumor cellsTumor typesTumor-associated inflammatory cellsCTLA-4 inhibitorsCell lung cancerRenal cell carcinoma cellsHigh response rateClin Cancer ResCell linesMelanoma tumor cellsPD-1Multivariable analysisNSCLC specimensInflammatory cellsLung cancerTissue microarrayResponse rateMeasurement of PD-1, TIM-3 and LAG-3 protein in non-small cell lung carcinomas (NSCLCs) with acquired resistance to PD-1 axis blockers.
Datar I, Mani N, Henick B, Wurtz A, Kaftan E, Herbst R, Rimm D, Gettinger S, Politi K, Schalper K. Measurement of PD-1, TIM-3 and LAG-3 protein in non-small cell lung carcinomas (NSCLCs) with acquired resistance to PD-1 axis blockers. Journal Of Clinical Oncology 2017, 35: e14611-e14611. DOI: 10.1200/jco.2017.35.15_suppl.e14611.Peer-Reviewed Original ResearchNon-small cell lung carcinomaTim-3PD-1LAG-3T cellsInhibitory receptorsAdvanced non-small cell lung carcinomaPD-1 axis blockadeHigh TIM-3Immune suppressive pathwaysImmune inhibitory receptorsCell lung carcinomaMembranous staining patternPre-treatment samplesWhole tissue sectionsWhole tumor areaClinical responseMost patientsAxis blockadeLow levelsLung carcinomaT lymphocytesMultiplex immunofluorescenceHigh levelsSuppressive pathways
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 value