2025
IL-4 mediated TAP2 downregulation is a dominant and reversible mechanism of immune evasion and immunotherapy resistance in non-small cell lung cancer
Ranjan K, Rajendran B, Deen I, Costantini A, de Rodas M, Desai S, Scallo F, Gianino N, Ferrone S, Schalper K. IL-4 mediated TAP2 downregulation is a dominant and reversible mechanism of immune evasion and immunotherapy resistance in non-small cell lung cancer. Molecular Cancer 2025, 24: 80. PMID: 40091029, PMCID: PMC11912681, DOI: 10.1186/s12943-025-02276-z.Peer-Reviewed Original ResearchThis study investigates IL-4's role in TAP2 downregulation as a reversible mechanism of immune evasion and resistance to immunotherapy in non-small cell lung cancer, highlighting potential therapeutic strategies to restore TAP2 expression and enhance treatment efficacy.
2022
148 TAP2 deficiency mediates adaptive immune evasion and immunotherapy resistance in human non-small cell lung cancer
Ranjan K, Deen I, Rodas M, Gianino N, Ferrone S, Schalper K. 148 TAP2 deficiency mediates adaptive immune evasion and immunotherapy resistance in human non-small cell lung cancer. 2022, a161-a161. DOI: 10.1136/jitc-2022-sitc2022.0148.Peer-Reviewed Original ResearchNon-small cell lung cancerHuman non-small cell lung cancerCell lung cancerAdaptive immune evasionImmunotherapy resistanceLung cancerImmune evasionCancerQuantitative tissue analysis and role of myeloid cells in non-small cell lung cancer
Henick BS, Villarroel-Espindola F, Datar I, Sanmamed MF, Yu J, Desai S, Li A, Aguirre-Ducler A, Syrigos K, Rimm DL, Chen L, Herbst RS, Schalper KA. Quantitative tissue analysis and role of myeloid cells in non-small cell lung cancer. Journal For ImmunoTherapy Of Cancer 2022, 10: e005025. PMID: 35793873, PMCID: PMC9260844, DOI: 10.1136/jitc-2022-005025.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerSquamous cell carcinomaHuman non-small cell lung cancerMyeloid cell subsetsCell lung cancerHLA-DRLung adenocarcinomaMyeloid cellsCell subsetsLung cancerLung tissueQuantitative immunofluorescenceNon-tumor lung tissuesIndependent NSCLC cohortsLevels of CD68Multiplexed quantitative immunofluorescenceProinflammatory myeloid cellsHLA-DR expressionM1-like macrophagesImmature myeloid cell populationMyeloid cell populationsKRAS mutant tumorsNormal lung tissuesTumor epithelial cellsNon-tumor lung
2021
Tumor Microenvironment: Immune Effector and Suppressor Imbalance
Sheehan K, Schalper K. Tumor Microenvironment: Immune Effector and Suppressor Imbalance. Current Cancer Research 2021, 1-25. DOI: 10.1007/978-3-030-74028-3_1.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsTumor microenvironmentNon-small cell lung cancerHuman non-small cell lung cancerCell lung cancerImmune evasion pathwaysPatient selection strategiesImmune cell interactionsBroad clinical useAnti-cancer therapyMechanism of actionCheckpoint inhibitorsImmune stimulatoryLung cancerIndividual patientsImmune featuresCurrent evidenceImmune effectorsTherapeutic targetingClinical useFuture cancer therapeuticsSuppressor signalsCancer therapeuticsCell interactionsPatients
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
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
The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer
Cascone T, Xu L, Lin HY, Liu W, Tran HT, Liu Y, Howells K, Haddad V, Hanrahan E, Nilsson MB, Cortez MA, Giri U, Kadara H, Saigal B, Park YY, Peng W, Lee JS, Ryan AJ, Jüergensmeier JM, Herbst RS, Wang J, Langley RR, Wistuba II, Lee JJ, Heymach JV. The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer. Clinical Cancer Research 2017, 23: 5489-5501. PMID: 28559461, PMCID: PMC5600821, DOI: 10.1158/1078-0432.ccr-16-3216.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarcinoma, Non-Small-Cell LungCell Line, TumorClinical Trials, Phase II as TopicClinical Trials, Phase III as TopicDisease Models, AnimalDrug Resistance, NeoplasmGene Expression ProfilingHepatocyte Growth FactorHumansHypoxiaKaplan-Meier EstimateLung NeoplasmsMaleMiceMolecular Targeted TherapyMulticenter Studies as TopicNeovascularization, PathologicPrognosisProtein Kinase InhibitorsProto-Oncogene Proteins c-metReceptors, Vascular Endothelial Growth FactorSignal TransductionXenograft Model Antitumor AssaysConceptsNon-small cell lung cancerHepatocyte growth factorC-MetHGF/c-Met pathwayHuman non-small cell lung cancerResistance of NSCLCAngiogenic factor levelsHGF plasma levelsCancer cellsTumor microvascular densityCell lung cancerEffect of therapyTortuous blood vesselsTumor vascular bedC-Met pathwayTyrosine kinase inhibitorsTumor-associated stromaClin Cancer ResHuman lung adenocarcinomaMurine xenograft modelVEGFR-TKIClinical outcomesLung cancerPlasma levelsMicrovascular density
2014
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution
de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, Jamal-Hanjani M, Shafi S, Murugaesu N, Rowan AJ, Grönroos E, Muhammad MA, Horswell S, Gerlinger M, Varela I, Jones D, Marshall J, Voet T, Van Loo P, Rassl DM, Rintoul RC, Janes SM, Lee SM, Forster M, Ahmad T, Lawrence D, Falzon M, Capitanio A, Harkins TT, Lee CC, Tom W, Teefe E, Chen SC, Begum S, Rabinowitz A, Phillimore B, Spencer-Dene B, Stamp G, Szallasi Z, Matthews N, Stewart A, Campbell P, Swanton C. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 2014, 346: 251-256. PMID: 25301630, PMCID: PMC4636050, DOI: 10.1126/science.1253462.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerOperable non-small cell lung cancerHuman non-small cell lung cancerSubclonal diversificationDriver mutationsCell lung cancerLung cancer evolutionFormer smokersDismal prognosisLung cancerTreatment successTumor latencyCarcinogen exposureCytidine deaminase activityCopy number alterationsClinical detectionSmokersIntratumor heterogeneityTumorsNumber alterationsRelative decreaseDeaminase activityMutationsTemporal dissectionPrognosis
2010
Combination Treatment with MEK and AKT Inhibitors Is More Effective than Each Drug Alone in Human Non-Small Cell Lung Cancer In Vitro and In Vivo
Meng J, Dai B, Fang B, Bekele BN, Bornmann WG, Sun D, Peng Z, Herbst RS, Papadimitrakopoulou V, Minna JD, Peyton M, Roth JA. Combination Treatment with MEK and AKT Inhibitors Is More Effective than Each Drug Alone in Human Non-Small Cell Lung Cancer In Vitro and In Vivo. PLOS ONE 2010, 5: e14124. PMID: 21124782, PMCID: PMC2993951, DOI: 10.1371/journal.pone.0014124.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisBenzimidazolesCarcinoma, Non-Small-Cell LungCell CycleCell Line, TumorCell SurvivalDose-Response Relationship, DrugDrug SynergismFemaleHeterocyclic Compounds, 3-RingHumansLung NeoplasmsMiceMice, Inbred BALB CMice, NudeMitogen-Activated Protein Kinase KinasesProto-Oncogene Proteins c-aktSignal TransductionSurvival AnalysisTumor BurdenXenograft Model Antitumor AssaysConceptsNon-small cell lung cancerCell lung cancerCombination of AZD6244Lung cancer cell linesCombination therapyLung cancerCancer cell linesTumor growthTumor tissueHuman non-small cell lung cancerLung cancer cell growthCell linesHuman lung cancer cell linesSingle drug treatmentSynergistic antitumor activityHuman lung tumorsAnimal survival timeMean animal survival timeCancer cell growthXenograft tumor growthP-AKT expressionLung tumorsDrug treatmentDrug combinationsSurvival time
2007
Targeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non–Small-Cell Lung Cancer
Shibuya K, Komaki R, Shintani T, Itasaka S, Ryan A, Jürgensmeier JM, Milas L, Ang K, Herbst RS, O'Reilly MS. Targeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non–Small-Cell Lung Cancer. International Journal Of Radiation Oncology • Biology • Physics 2007, 69: 1534-1543. PMID: 17889445, PMCID: PMC2151850, DOI: 10.1016/j.ijrobp.2007.07.2350.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationCombined Modality TherapyDNA RepairEpidermal Growth FactorErbB ReceptorsFeasibility StudiesHumansLung NeoplasmsMaleMiceMice, NudeNeovascularization, PathologicPiperidinesPleural EffusionQuinazolinesRadiation ToleranceRadiation-Sensitizing AgentsReceptors, Vascular Endothelial Growth FactorVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Xenograft Model Antitumor AssaysConceptsVascular endothelial growth factor receptor 2Epidermal growth factor receptorLung cancerHuman lung cancerOrthotopic modelRadiation therapyHuman lung adenocarcinoma cellsLung adenocarcinoma cellsConventional therapyAntitumor effectsOrthotopic human lung cancer modelNon-small cell lung cancerHuman non-small cell lung cancerHuman lung cancer modelAdenocarcinoma cellsGrowth factor receptor 2Lung tumor burdenLung cancer modelEndothelial growth factor receptor 2Pleural effusion formationFactor receptor 2Basic fibroblast growth factorMatrix metalloproteinase-2Human lung adenocarcinomaSublethal damage repairEpidermal Growth Factor Receptor Mutants from Human Lung Cancers Exhibit Enhanced Catalytic Activity and Increased Sensitivity to Gefitinib
Mulloy R, Ferrand A, Kim Y, Sordella R, Bell D, Haber D, Anderson K, Settleman J. Epidermal Growth Factor Receptor Mutants from Human Lung Cancers Exhibit Enhanced Catalytic Activity and Increased Sensitivity to Gefitinib. Cancer Research 2007, 67: 2325-2330. PMID: 17332364, DOI: 10.1158/0008-5472.can-06-4293.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorEpidermal growth factor receptor mutantMultiple levels in vivoIn vitro kinase assayEpidermal growth factor receptor functionPurified recombinant proteinWild-type epidermal growth factor receptorSensitivity to kinase inhibitionNon-small cell lung cancerCOOH-terminal tyrosineHuman non-small cell lung cancerIncreased sensitivity to gefitinibSensitivity to gefitinibCell lung cancerAutophosphorylation activityGrowth factor receptorCell-based studiesEGFR kinase inhibitorsCytoplasmic domainRecombinant proteinsKinase assayEnzyme functionDownstream effectorsMutantsKinase activity
2006
Mutational Analysis of PUMA Gene in Non-small Cell Lung Cancers
Yoo N, Lee J, Lee S, Lee S. Mutational Analysis of PUMA Gene in Non-small Cell Lung Cancers. Journal Of Lung Cancer 2006, 5: 92-95. DOI: 10.6058/jlc.2006.5.2.92.Peer-Reviewed Original ResearchSingle-strand conformation polymorphismSplice siteNon-small cell lung cancerPUMA geneProapoptotic memberCoding regionHuman non-small cell lung cancerMembers of Bcl-2 familyPathogenesis of human non-small cell lung cancersMutation analysisPolymerase chain reaction (PCR)-based single-strand conformation polymorphismProapoptotic member of Bcl-2 familyCell lung cancerBcl-2 familySomatic mutationsGenetic alterationsDeregulation of apoptosisHuman cancersPCR-SSCP analysisPUMA protein expressionApoptosis-related genesLung cancerDevelopment of human cancersConformation polymorphismPCR-SSCPMutational Analysis of Pro-apoptotic BAD Gene in Non-small Cell Lung Cancer
Lee J, Soung Y, Nam S, Lee J, Yoo N, Lee S. Mutational Analysis of Pro-apoptotic BAD Gene in Non-small Cell Lung Cancer. Journal Of Lung Cancer 2006, 5: 35-38. DOI: 10.6058/jlc.2006.5.1.35.Peer-Reviewed Original ResearchBcl-xL/Bcl-2-associated death promoterSingle-strand conformation polymorphismPro-apoptotic membersSplice siteNon-small cell lung cancerCoding regionBad genesPro-apoptotic member of Bcl-2 familyHuman non-small cell lung cancerMembers of Bcl-2 familyPathogenesis of human non-small cell lung cancersMutation analysisPolymerase chain reaction (PCR)-based single-strand conformation polymorphismCell lung cancerBcl-2 familySomatic mutationsGenetic alterationsIntrinsic apoptosis pathwayDeregulation of apoptosisHuman cancersPCR-SSCP analysisApoptosis-related genesDevelopment of human cancersMechanisms of cancer developmentLung cancer
2004
Targeted therapy against VEGFR and EGFR signaling with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic mouse model of human non-small cell lung cancer
Shibuya K, Komaki R, Wu W, Shintani T, Itasaka S, Isobe T, Ryan A, Herbst R, O’Reilly M. Targeted therapy against VEGFR and EGFR signaling with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic mouse model of human non-small cell lung cancer. International Journal Of Radiation Oncology • Biology • Physics 2004, 60: s149-s150. DOI: 10.1016/j.ijrobp.2004.06.061.Peer-Reviewed Original Research159 Blocking VEGF and EGF receptor signaling with ZD6474 sensitizes human non-small cell lung cancer to chemotherapy with paclitaxel
Wu W, Shintani T, O'Reilly M, Herbst R. 159 Blocking VEGF and EGF receptor signaling with ZD6474 sensitizes human non-small cell lung cancer to chemotherapy with paclitaxel. European Journal Of Cancer Supplements 2004, 2: 50-51. DOI: 10.1016/s1359-6349(04)80167-8.Peer-Reviewed Original ResearchNon-small cell lung cancerHuman non-small cell lung cancerCell lung cancerLung cancerEGF receptorChemotherapyZD6474CancerPaclitaxelTargeted therapy against VEGFR and EGFR signaling with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic mouse model of human non-small cell lung cancer
SHIBUYA K, KOMAKI R, WU W, SHINTANI T, ITASAKA S, ISOBE T, RYAN A, HERBST R, OREILLY M. Targeted therapy against VEGFR and EGFR signaling with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic mouse model of human non-small cell lung cancer. International Journal Of Radiation Oncology • Biology • Physics 2004, 60: s149-s150. DOI: 10.1016/s0360-3016(04)01118-6.Peer-Reviewed Original Research
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