2023
Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma.
Horowitch B, Lee D, Ding M, Martinez-Morilla S, Aung T, Ouerghi F, Wang X, Wei W, Damsky W, Sznol M, Kluger H, Rimm D, Ishizuka J. Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma. Clinical Cancer Research 2023, 29: 2908-2918. PMID: 37233452, PMCID: PMC10524955, DOI: 10.1158/1078-0432.ccr-23-0215.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsHuman melanoma cell linesMelanoma cell linesPD-L1Validation cohortYale-New Haven HospitalCombination of ipilimumabPD-L1 markersImmune checkpoint blockadePD-L1 biomarkerNew Haven HospitalSTAT1 levelsCell linesWestern blot analysisCheckpoint inhibitorsCheckpoint blockadeClinical responseOverall survivalImproved survivalResistance of cancersMetastatic melanomaMelanoma responsePredict responseTreatment responseDistinct patterns
2021
KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements
Zhang SM, Cai WL, Liu X, Thakral D, Luo J, Chan LH, McGeary MK, Song E, Blenman KRM, Micevic G, Jessel S, Zhang Y, Yin M, Booth CJ, Jilaveanu LB, Damsky W, Sznol M, Kluger HM, Iwasaki A, Bosenberg MW, Yan Q. KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements. Nature 2021, 598: 682-687. PMID: 34671158, PMCID: PMC8555464, DOI: 10.1038/s41586-021-03994-2.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorDNA-Binding ProteinsEpigenesis, GeneticGene SilencingHeterochromatinHistone-Lysine N-MethyltransferaseHumansInterferon Type IJumonji Domain-Containing Histone DemethylasesMaleMelanomaMiceMice, Inbred C57BLMice, KnockoutNuclear ProteinsRepressor ProteinsRetroelementsTumor EscapeConceptsImmune checkpoint blockadeImmune evasionCheckpoint blockadeImmune responseAnti-tumor immune responseRobust adaptive immune responseTumor immune evasionAnti-tumor immunityAdaptive immune responsesType I interferon responseDNA-sensing pathwayMouse melanoma modelImmunotherapy resistanceMost patientsCurrent immunotherapiesTumor immunogenicityImmune memoryMelanoma modelCytosolic RNA sensingRole of KDM5BConsiderable efficacyInterferon responseImmunotherapyEpigenetic therapyBlockade
2019
Multiplex quantitative analysis of cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma
Wong PF, Wei W, Gupta S, Smithy JW, Zelterman D, Kluger HM, Rimm DL. Multiplex quantitative analysis of cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2019, 7: 194. PMID: 31337426, PMCID: PMC6651990, DOI: 10.1186/s40425-019-0675-0.Peer-Reviewed Original ResearchConceptsProgression-free survivalBest overall responseSmooth muscle actinOverall survivalCell countQuantitative immunofluorescenceImmune markersImmunotherapy outcomesMelanoma patientsSignificant progression-free survivalAnti-PD-1 therapyAbsence of immunotherapyPretreatment tumor specimensImmune checkpoint blockadeCell death 1Cancer-associated fibroblast (CAF) populationNegative prognostic biomarkerCancer-associated fibroblastsWhole tissue sectionsOverall responseOS associationCAF parametersCheckpoint blockadeImmune dysregulationDeath-1
2018
Early B cell changes predict autoimmunity following combination immune checkpoint blockade
Das R, Bar N, Ferreira M, Newman AM, Zhang L, Bailur JK, Bacchiocchi A, Kluger H, Wei W, Halaban R, Sznol M, Dhodapkar MV, Dhodapkar KM. Early B cell changes predict autoimmunity following combination immune checkpoint blockade. Journal Of Clinical Investigation 2018, 128: 715-720. PMID: 29309048, PMCID: PMC5785243, DOI: 10.1172/jci96798.Peer-Reviewed Original ResearchConceptsCombination checkpoint blockadeB cell changesB cellsCheckpoint blockadeCell changesCombination immune checkpoint blockadeB-cell receptor sequencingRisk of irAEsImmune checkpoint blockadeCell receptor sequencingB cell activationTreatment-induced changesCCB therapyAdverse eventsPD1 expressionPD1 receptorGrade 3PatientsCell activationEarly changesSingle-cell RNA sequencingTherapyPreemptive strategyCancer therapyIrAEs
2017
Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control
An Y, Jiang W, Kim BYS, Qian JM, Tang C, Fang P, Logan J, D'Souza NM, Haydu LE, Wang XA, Hess KR, Kluger H, Glitza IC, Mahajan A, Welsh JW, Lin SH, Yu JB, Davies MA, Hwu P, Sulman EP, Brown PD, Chiang VLS, Li J. Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiotherapy And Oncology 2017, 125: 80-88. PMID: 28916225, DOI: 10.1016/j.radonc.2017.08.009.Peer-Reviewed Original ResearchConceptsIntracranial disease controlNew brain metastasesIntracranial controlStereotactic radiosurgeryBrain metastasesOverall survivalDisease controlLymphocyte countMulti-institutional retrospective analysisYale-New Haven HospitalMD Anderson cohortMelanoma brain metastasesAbsolute lymphocyte countAntitumor immune responseImmune checkpoint blockadeMetastatic melanoma patientsComplete blood countTumor-specific antigensIndependent validation cohortMulti-institutional studyIpilimumab therapyMedian followLast doseCheckpoint blockadeIntracranial recurrenceChanges in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients
Sanmamed MF, Perez-Gracia JL, Schalper KA, Fusco JP, Gonzalez A, Rodriguez-Ruiz ME, Oñate C, Perez G, Alfaro C, Martín-Algarra S, Andueza MP, Gurpide A, Morgado M, Wang J, Bacchiocchi A, Halaban R, Kluger H, Chen L, Sznol M, Melero I. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients. Annals Of Oncology 2017, 28: 1988-1995. PMID: 28595336, PMCID: PMC5834104, DOI: 10.1093/annonc/mdx190.Peer-Reviewed Original ResearchConceptsSerum IL-8 levelsIL-8 levelsCell lung cancer patientsLung cancer patientsNSCLC patientsCancer patientsMelanoma patientsPD1/PD-L1 therapyAnti-PD-1 treatmentAnti-PD-1 blockadeSerum interleukin-8 levelsPD-L1 therapyImmune checkpoint blockadeInterleukin-8 levelsLonger overall survivalBiomarkers of responseMann-Whitney testCheckpoint blockadeFirst doseOverall survivalStrength of associationClinical benefitReceiver operation characteristic curveMetastatic melanomaSurrogate biomarker
2015
Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo. The Journal Of Immunology 2015, 194: 950-959. PMID: 25539810, PMCID: PMC4380504, DOI: 10.4049/jimmunol.1401686.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntigens, SurfaceAntineoplastic Combined Chemotherapy ProtocolsCTLA-4 AntigenCytokinesGene Expression ProfilingGene Expression Regulation, NeoplasticHumansImmunophenotypingIpilimumabLymphocytes, Tumor-InfiltratingNeoplasmsNivolumabProgrammed Cell Death 1 ReceptorSignal TransductionT-Lymphocyte SubsetsConceptsPD-1T cellsCTLA-4Checkpoint blockadeCombination therapyReceptor occupancyCombination immune checkpoint blockadeCTLA-4 immune checkpointsPD-1 receptor occupancyTransitional memory T cellsAnti-PD-1 therapyAnti CTLA-4Immune-based combinationsPD-1 blockadeSoluble IL-2RImmune checkpoint blockadeNK cell functionMemory T cellsTherapy-induced changesT cell activationTumor T cellsHuman T cellsRemarkable antitumor effectImmunologic changesImmunologic effects
2014
Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205
Dhodapkar MV, Sznol M, Zhao B, Wang D, Carvajal RD, Keohan ML, Chuang E, Sanborn RE, Lutzky J, Powderly J, Kluger H, Tejwani S, Green J, Ramakrishna V, Crocker A, Vitale L, Yellin M, Davis T, Keler T. Induction of Antigen-Specific Immunity with a Vaccine Targeting NY-ESO-1 to the Dendritic Cell Receptor DEC-205. Science Translational Medicine 2014, 6: 232ra51. PMID: 24739759, PMCID: PMC6151129, DOI: 10.1126/scitranslmed.3008068.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntigens, CDAntigens, NeoplasmCancer VaccinesCytokinesDendritic CellsDose-Response Relationship, ImmunologicEpitopesFemaleHumansImmunity, CellularImmunity, HumoralImmunoglobulin GInterferon-gammaLectins, C-TypeLymphocyte SubsetsMaleMembrane ProteinsMiddle AgedMinor Histocompatibility AntigensReceptors, Cell SurfaceT-LymphocytesVaccinationConceptsNY-ESO-1Immune checkpoint inhibitorsDendritic cellsToll-like receptorsTumor regressionNY-ESO-1-expressing tumorsTumor antigen NY-ESO-1Presence of DCsRobust antigen-specific immune responsesAntigen-specific immune responsesAntigen NY-ESO-1Combination immunotherapy strategiesStabilization of diseaseGrade 3 toxicityObjective tumor regressionImmune checkpoint blockadeT cell immunityAntigen-specific immunityPhase 1 trialTumor-associated antigensReceptor-specific monoclonal antibodyCheckpoint inhibitorsAdvanced malignanciesCheckpoint blockadeMedian duration