2024
High-throughput transcriptome profiling indicates ribosomal RNAs to be associated with resistance to immunotherapy in non-small cell lung cancer (NSCLC)
Moutafi M, Bates K, Aung T, Milian R, Xirou V, Vathiotis I, Gavrielatou N, Angelakis A, Schalper K, Salichos L, Rimm D. High-throughput transcriptome profiling indicates ribosomal RNAs to be associated with resistance to immunotherapy in non-small cell lung cancer (NSCLC). Journal For ImmunoTherapy Of Cancer 2024, 12: e009039. PMID: 38857914, PMCID: PMC11168162, DOI: 10.1136/jitc-2024-009039.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerImmune checkpoint inhibitorsProgrammed cell death protein 1Associated with OSCell lung cancerTissue microarray spotsTissue microarrayValidation cohortLung cancerNon-small cell lung cancer treated with immune checkpoint inhibitorsAssociated with resistance to immunotherapyCell death protein 1Resistance to immunotherapyAssociated with PFSProgression-free survivalSecreted frizzled-related protein 2Cox proportional-hazards model analysisCheckpoint inhibitorsImmunotherapy strategiesTumor compartmentsRetrospective cohortDiscovery cohortLong-term benefitsPatientsCD68HLA class-I antigen presentation machinery (APM) alterations mediate immune evasion in lung cancer brain metastases.
Vilariño N, Lopez De Rodas M, Ranjan K, Costantini A, Villalba M, Lu B, Kravitz C, Nadal E, Goldberg S, Nguyen D, Schalper K. HLA class-I antigen presentation machinery (APM) alterations mediate immune evasion in lung cancer brain metastases. Journal Of Clinical Oncology 2024, 42: e14014-e14014. DOI: 10.1200/jco.2024.42.16_suppl.e14014.Peer-Reviewed Original ResearchLung cancer brain metastasisPrimary lung tumorsTumor-infiltrating lymphocytesImmune checkpoint inhibitorsCancer brain metastasesAntigen presentation machineryB2M expressionIFN-gBrain metastasesB2MImmune evasionAssociated with shorter overall survivalMultiplexed quantitative immunofluorescenceM expressionExpression of B2MB2M levelsExpression of pSTAT1Shorter overall survivalUnfavorable clinical featuresNo significant associationAssociated with unfavorable clinical featuresCheckpoint inhibitorsImmunotherapy resistanceProperties of tumorsPresentation machinery
2023
International Association for the Study of Lung Cancer Study of Reproducibility in Assessment of Pathologic Response in Resected Lung Cancers After Neoadjuvant Therapy
Dacic S, Travis W, Redman M, Saqi A, Cooper W, Borczuk A, Chung J, Glass C, Lopez J, Roden A, Sholl L, Weissferdt A, Posadas J, Walker A, Zhu H, Wijeratne M, Connolly C, Wynes M, Bota-Rabassedas N, Sanchez-Espiridion B, Lee J, Berezowska S, Chou T, Kerr K, Nicholson A, Poleri C, Schalper K, Tsao M, Carbone D, Ready N, Cascone T, Heymach J, Sepesi B, Shu C, Rizvi N, Sonett J, Altorki N, Provencio M, Bunn P, Kris M, Belani C, Kelly K, Wistuba I, Committee I. International Association for the Study of Lung Cancer Study of Reproducibility in Assessment of Pathologic Response in Resected Lung Cancers After Neoadjuvant Therapy. Journal Of Thoracic Oncology 2023, 18: 1290-1302. PMID: 37702631, DOI: 10.1016/j.jtho.2023.07.017.Peer-Reviewed Original ResearchConceptsPathologic responseViable tumorNeoadjuvant therapyLung cancerClinical trialsInter-rater agreementNeoadjuvant immune checkpoint inhibitorsClinical trial end pointsResected Lung CancerImmune checkpoint inhibitorsTrial end pointsInvasive mucinous adenocarcinomaResidual viable tumorTumor bed areaEosin-stained slidesLung cancer studiesCheckpoint inhibitorsNeoadjuvant treatmentMucinous adenocarcinomaPathologic evaluationStromal inflammationPulmonary pathologistsTumor bedLung tumorsCommon reasonNeuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy
Biswas S, Kang K, Ng K, Radivoyevitch T, Schalper K, Zhang H, Lindner D, Thomas A, MacPherson D, Gastman B, Schrump D, Wong K, Velcheti V, Saunthararajah Y. Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy. Cell Reports 2023, 42: 113016. PMID: 37597186, PMCID: PMC10528072, DOI: 10.1016/j.celrep.2023.113016.Peer-Reviewed Original ResearchConceptsSmall cell lung cancerNon-cytotoxic therapiesImmune checkpoint inhibitorsCell lung cancerDNA methyltransferase 1SCLC cellsCytotoxic chemotherapyLung cancerDisseminated small cell lung cancerRepression marksSurvival of miceLineage commitmentCheckpoint inhibitorsResistant therapiesMaster transcription factorMaturation arrestTherapyTranscription factorsClinical compoundsMethyltransferase 1DNMT1 knockdownChemotherapyLineage maturationTranslocation 2Neuroendocrine lineageBSBM-16 HLA CLASS-I ANTIGEN PRESENTATION MACHINERY AND IFN-γ PATHWAY ALTERATIONS IN LUNG CANCER BRAIN METASTASES
Vilarino N, de Rodas M, Lu B, Goldberg S, Schalper K. BSBM-16 HLA CLASS-I ANTIGEN PRESENTATION MACHINERY AND IFN-γ PATHWAY ALTERATIONS IN LUNG CANCER BRAIN METASTASES. Neuro-Oncology Advances 2023, 5: iii4-iii4. PMCID: PMC10402438, DOI: 10.1093/noajnl/vdad070.012.Peer-Reviewed Original ResearchLung cancer brain metastasesPrimary lung tumorsImmune checkpoint inhibitorsCancer brain metastasesBrain metastasesPresentation machineryClinicopathologic variablesHLA classTumor cell PD-L1 expressionBackground Immune checkpoint inhibitorsLocal adaptive immune responseHLA Class I AntigenPD-L1 expressionDuration of responseB2MAdaptive immune responsesDistinct immunomodulatory propertiesImmune evasion mechanismsClass I AntigenIFN-γ signalingIRF-1Interferon regulatory factor 1Checkpoint inhibitorsMost patientsWorse survivalDeveloping a definition of immune exclusion in cancer: results of a modified Delphi workshop
Clifton G, Rothenberg M, Ascierto P, Begley G, Cecchini M, Eder J, Ghiringhelli F, Italiano A, Kochetkova M, Li R, Mechta-Grigoriou F, Pai S, Provenzano P, Puré E, Ribas A, Schalper K, Fridman W. Developing a definition of immune exclusion in cancer: results of a modified Delphi workshop. Journal For ImmunoTherapy Of Cancer 2023, 11: e006773. PMID: 37290925, PMCID: PMC10254706, DOI: 10.1136/jitc-2023-006773.Peer-Reviewed Original ResearchConceptsImmune exclusionTumor microenvironmentCheckpoint inhibitorsImmune checkpoint inhibitorsMinority of patientsT cell infiltrationPoor clinical outcomeImmune regulatory pathwaysEffective treatment approachDevelopment of treatmentsVariety of cancersLack of responseCheckpoint therapyImmune profileClinical outcomesClinical benefitPatient outcomesCancer expertsCancer histologyT cellsConsensus definitionTreatment approachesCancer typesRound questionnaireDelphi processRole of HLA class-I antigen peptide loading complex components in immune evasion and treatment sensitivity in human lung cancer.
Costantini A, Ranjan K, Ferrone S, Schalper K. Role of HLA class-I antigen peptide loading complex components in immune evasion and treatment sensitivity in human lung cancer. Journal Of Clinical Oncology 2023, 41: 2623-2623. DOI: 10.1200/jco.2023.41.16_suppl.2623.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsHLA classSelective downregulationShorter OSICI resistanceMarker levelsStromal cellsLow marker levelTumor antigen recognitionEffector T cellsT cell infiltrationT cell levelsProtein levelsPeptide loading complexEarly-stage tumorsHuman lung cancerPeptide-HLA complexesLevels of TAPDeterminants of sensitivityLow CD8Checkpoint inhibitorsHuman NSCLCPresentation machineryClinicopathologic variablesLung cancerGenomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer
Ravi A, Hellmann M, Arniella M, Holton M, Freeman S, Naranbhai V, Stewart C, Leshchiner I, Kim J, Akiyama Y, Griffin A, Vokes N, Sakhi M, Kamesan V, Rizvi H, Ricciuti B, Forde P, Anagnostou V, Riess J, Gibbons D, Pennell N, Velcheti V, Digumarthy S, Mino-Kenudson M, Califano A, Heymach J, Herbst R, Brahmer J, Schalper K, Velculescu V, Henick B, Rizvi N, Jänne P, Awad M, Chow A, Greenbaum B, Luksza M, Shaw A, Wolchok J, Hacohen N, Getz G, Gainor J. Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer. Nature Genetics 2023, 55: 807-819. PMID: 37024582, PMCID: PMC10181943, DOI: 10.1038/s41588-023-01355-5.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerAdvanced non-small cell lung cancerCell lung cancerLung cancerAnti-PD-1/PD-L1 agentsCheckpoint blockade responsePD-L1 agentsTumor intrinsic subtypesCheckpoint inhibitorsCheckpoint blockadeTreatment landscapeImmunotherapy outcomesBlockade responseCohortBiological determinantsGenomic subgroupsEnhanced responseMolecular featuresWhole exomeCancerProminent associationOutcomesAssociationResponseNumber of associations
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
2021
240 Discovery of biomarkers of resistance to immune checkpoint blockade in non-small-cell lung cancer (NSCLC) using high-plex digital spatial profiling
Moutafi M, Martinez-Morilla S, Divakar P, Vathiotis I, Gavrielatou N, Aung T, Yaghoobi V, Fernandez A, Fraile J, Schalper K, Rimm D. 240 Discovery of biomarkers of resistance to immune checkpoint blockade in non-small-cell lung cancer (NSCLC) using high-plex digital spatial profiling. 2021, a258-a258. DOI: 10.1136/jitc-2021-sitc2021.240.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsPre-treatment samplesQuantitative immunofluorescencePredictive biomarkersLung cancerHigh PD-L1 expressionExpression of CD66bInitial biomarker discoveryOperable NSCLC patientsStromal immune cellsTwo-sided significance levelPD-L1 expressionImmune checkpoint blockadeRole of neutrophilsCell lung cancerPotential predictive biomarkersGood predictive valueDigital spatial profilingDigital Spatial ProfilerCohort validationICI therapyCheckpoint inhibitorsCheckpoint blockadeNSCLC cohortNSCLC patientsTumor 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
2018
Molecular Determinants of Response to Anti–Programmed Cell Death (PD)-1 and Anti–Programmed Death-Ligand (PD-L)-Ligand 1 Blockade in Patients With Non–Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing
Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, Plodkowski A, Long N, Sauter JL, Rekhtman N, Hollmann T, Schalper KA, Gainor JF, Shen R, Ni A, Arbour KC, Merghoub T, Wolchok J, Snyder A, Chaft JE, Kris MG, Rudin CM, Socci ND, Berger MF, Taylor BS, Zehir A, Solit DB, Arcila ME, Ladanyi M, Riely GJ, Schultz N, Hellmann MD. Molecular Determinants of Response to Anti–Programmed Cell Death (PD)-1 and Anti–Programmed Death-Ligand (PD-L)-Ligand 1 Blockade in Patients With Non–Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. Journal Of Clinical Oncology 2018, 36: jco.2017.75.338. PMID: 29337640, PMCID: PMC6075848, DOI: 10.1200/jco.2017.75.3384.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsDurable clinical benefitTumor mutation burdenPD-L1 expressionCell lung cancerTargeted Next-Generation SequencingWhole-exome sequencingLung cancerNext-generation sequencingPartial response/stable diseaseUse of ICIsAnti-programmed death-1Response/stable diseaseSolid Tumors version 1.1Anti-programmed cell deathProgression-free survivalResponse Evaluation CriteriaSubset of patientsPredictors of responseMultivariable predictive modelDetailed clinical annotationLack of benefitStable diseaseCheckpoint inhibitorsDurable responses
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 mutations
2015
Objective Measurement and Clinical Significance of TILs in Non–Small Cell Lung Cancer
Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, Herbst RS, Rimm DL. Objective Measurement and Clinical Significance of TILs in Non–Small Cell Lung Cancer. Journal Of The National Cancer Institute 2015, 107: dju435. PMID: 25650315, PMCID: PMC4565530, DOI: 10.1093/jnci/dju435.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CD20Carcinoma, Non-Small-Cell LungCD3 ComplexCD8 AntigensConfounding Factors, EpidemiologicFluorescent DyesHumansIndolesKaplan-Meier EstimateLung NeoplasmsLymphocytes, Tumor-InfiltratingMicroscopy, FluorescencePredictive Value of TestsRetrospective StudiesT-Lymphocytes, CytotoxicConceptsTumor-infiltrating lymphocytesLevels of CD3TIL subtypesMultivariable analysisTumor sizeLonger survivalAssociation of TILsLevel of TILsNon-small cell lung cancerNon-small cell lung cancer samplesLocal immune effectsClinico-pathologic characteristicsImmune checkpoint inhibitorsCell lung cancerCell lung cancer samplesLung cancer samplesDifferent tumor compartmentsObjective measurementsElevated CD3High CD20TIL markersTIL subpopulationsCheckpoint inhibitorsSmoking historyHistology type