2023
Manipulating mitochondrial electron flow enhances tumor immunogenicity
Mangalhara K, Varanasi S, Johnson M, Burns M, Rojas G, Esparza Moltó P, Sainz A, Tadepalle N, Abbott K, Mendiratta G, Chen D, Farsakoglu Y, Kunchok T, Hoffmann F, Parisi B, Rincon M, Vander Heiden M, Bosenberg M, Hargreaves D, Kaech S, Shadel G. Manipulating mitochondrial electron flow enhances tumor immunogenicity. Science 2023, 381: 1316-1323. PMID: 37733872, PMCID: PMC11034774, DOI: 10.1126/science.abq1053.Peer-Reviewed Original ResearchConceptsElectron transport chainMethylation-controlled J proteinMitochondrial electron transport chainElectron flowMitochondrial electron flowJ-proteinsEpigenetic activationTransport chainMitochondrial respirationTumor growthPresentation genesElectron entryNoncancer cellsMelanoma tumor growthCommon mechanismTherapeutic potentialGenesRelative contributionProteinGrowthKnockoutAntigen presentationRespirationT cell-mediated killingExpressionIL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory
Micevic G, Daniels A, Flem-Karlsen K, Park K, Talty R, McGeary M, Mirza H, Blackburn H, Sefik E, Cheung J, Hornick N, Aizenbud L, Joshi N, Kluger H, Iwasaki A, Bosenberg M, Flavell R. IL-7R licenses a population of epigenetically poised memory CD8+ T cells with superior antitumor efficacy that are critical for melanoma memory. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2304319120. PMID: 37459511, PMCID: PMC10372654, DOI: 10.1073/pnas.2304319120.Peer-Reviewed Original ResearchConceptsIL-7R expressionT cellsIL-7RAntitumor memorySuperior antitumor efficacyCell-based therapiesTumor-specific T cellsAntigen-specific T cellsAntitumor efficacyPowerful antitumor immune responseMarkers of exhaustionTumor-specific CD8Antitumor immune responseIndependent prognostic factorAntitumor immune memoryMemory T cellsMajor risk factorSuperior antitumor activityFunctional CD8Memory CD8Prognostic factorsSurgical resectionAdvanced melanomaLymph nodesNaive miceDeterminants of overall survival in patients with metastatic uveal melanoma
Demkowicz P, Pointdujour‐Lim R, Miguez S, Lee Y, Jones B, Barker C, Bosenberg M, Abramson D, Shoushtari A, Kluger H, Francis J, Sznol M, Bakhoum M. Determinants of overall survival in patients with metastatic uveal melanoma. Cancer 2023, 129: 3275-3286. PMID: 37382208, PMCID: PMC11149607, DOI: 10.1002/cncr.34927.Peer-Reviewed Original ResearchConceptsAnti-PD-1 therapyMetastatic uveal melanomaDeath hazard ratioImmune checkpoint inhibitorsOverall survivalHazard ratioUveal melanomaSurvival outcomesFemale sexCheckpoint inhibitorsECOG scoreValidation cohortEastern Cooperative Oncology Group performance status scaleGood baseline performance statusMetastatic uveal melanoma patientsMetastatic UM patientsImproved overall survivalMedian overall survivalBaseline performance statusBetter survival outcomesImproved survival outcomesPotential of immunotherapyWorse survival outcomesImmune checkpoint therapyKaplan-Meier analysisInterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma
Orlow I, Sadeghi K, Edmiston S, Kenney J, Lezcano C, Wilmott J, Cust A, Scolyer R, Mann G, Lee T, Burke H, Jakrot V, Shang P, Ferguson P, Boyce T, Ko J, Ngo P, Funchain P, Rees J, O’Connell K, Hao H, Parrish E, Conway K, Googe P, Ollila D, Moschos S, Hernando E, Hanniford D, Argibay D, Amos C, Lee J, Osman I, Luo L, Kuan P, Aurora A, Rothberg BE, Bosenberg M, Gerstenblith M, Thompson C, Bogner P, Gorlov I, Holmen S, Brunsgaard E, Saenger Y, Shen R, Seshan V, Nagore E, Ernstoff M, Busam K, Begg C, Thomas N, Berwick M, Consortium O. InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma. PLOS ONE 2023, 18: e0269324. PMID: 37011054, PMCID: PMC10069769, DOI: 10.1371/journal.pone.0269324.Peer-Reviewed Original ResearchConceptsEarly-stage melanomaPrimary melanomaMemorial Sloan-Kettering Cancer CenterDisease-specific survivalPredictors of survivalMulti-institutional settingSomatic mutationsPre-established protocolMiRNA expressionScreening failureMulticenter studyCancer CenterDownstream testingLimited tumor tissueNucleic acid qualityClinical databaseMulticenter researchTumor tissueMelanomaTumor samplesFFPE tumorsArchival tissueFFPE tissue blocksTissue blocksSuccess rateValidation of the Prognostic Usefulness of the Gene Expression Profiling Test in Patients with Uveal Melanoma
Miguez S, Lee R, Chan A, Demkowicz P, Jones B, Long C, Abramson D, Bosenberg M, Sznol M, Kluger H, Goldbaum M, Francis J, Pointdujour-Lim R, Bakhoum M. Validation of the Prognostic Usefulness of the Gene Expression Profiling Test in Patients with Uveal Melanoma. Ophthalmology 2023, 130: 598-607. PMID: 36739981, PMCID: PMC10619207, DOI: 10.1016/j.ophtha.2023.01.020.Peer-Reviewed Original ResearchConceptsMetastasis-free survivalRisk of metastasisClass 2 tumorsAdditional prognostic valueRate of metastasisPrognostic usefulnessTumor sizeTumor characteristicsPrognostic valueUveal melanomaGene expression profile testingMemorial Sloan-Kettering Cancer CenterGEP classificationCox hazard regression analysisYale-New Haven HospitalHazards regression analysisGene expression profiling testsNew Haven HospitalClass 1 tumorsGEP class 2Class 1AMean followTumor thicknessCancer CenterSurveillance protocol
2022
Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors.
Fenton S, Zannikou M, Ilut L, Fischietti M, Ji C, Oku C, Horvath C, Le Poole I, Bosenberg M, Bartom E, Kocherginsky M, Platanias L, Saleiro D. Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors. Molecular Cancer Research 2022, 21: 332-344. PMID: 36573964, PMCID: PMC10073316, DOI: 10.1158/1541-7786.mcr-22-0684.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsImmunosuppressive genesCheckpoint inhibitorsImmunostimulatory genesAnti-programmed cell death protein 1 therapyPharmacologic inhibitionIFNγ-induced expressionMelanoma cellsMajority of patientsTreatment of patientsTreatment of melanomaMelanoma tumor growthDrug target inhibitionICI therapyDurable responsesPatient survivalMetastatic melanomaPatient outcomesPoor survivalResponse rateTumor growthIFNγOverexpression of ULK1Context-dependent mannerMelanomaLongitudinal single-cell analysis of a patient receiving adoptive cell therapy reveals potential mechanisms of treatment failure
Qu R, Kluger Y, Yang J, Zhao J, Hafler D, Krause D, Bersenev A, Bosenberg M, Hurwitz M, Lucca L, Kluger H. Longitudinal single-cell analysis of a patient receiving adoptive cell therapy reveals potential mechanisms of treatment failure. Molecular Cancer 2022, 21: 219. PMID: 36514045, PMCID: PMC9749221, DOI: 10.1186/s12943-022-01688-5.Peer-Reviewed Original ResearchConceptsAdoptive cell therapySingle-cell analysisDepth single-cell analysisSingle-cell RNAACT productsDisease progressionT-cell receptor sequencingCell therapyFamily genesFeatures of exhaustionMultiple tumor typesCell expansionGenesNew clonotypesTIL preparationsClonal cell expansionCytokine therapyTreatment failureSerial bloodClonesEffector functionsSerial samplesTumor typesCellular therapyTherapy
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
2018
PD‐L1 methylation regulates PD‐L1 expression and is associated with melanoma survival
Micevic G, Thakral D, McGeary M, Bosenberg M. PD‐L1 methylation regulates PD‐L1 expression and is associated with melanoma survival. Pigment Cell & Melanoma Research 2018, 32: 435-440. PMID: 30343532, PMCID: PMC6475614, DOI: 10.1111/pcmr.12745.Peer-Reviewed Original ResearchConceptsPD-L1 expressionDNA methylationPD-1/PD-L1 immune checkpointIndependent survival prognostic factorPD-L1 promoter methylationPD-L1 immune checkpointSurvival prognostic factorsPD-L1 promoterPromoter DNA methylationOverall survivalImmune checkpointsPrognostic factorsMelanoma patientsMelanoma survivalEpigenetic mechanismsTranscriptional phenotypeClinical importanceMelanomaCpG lociMethylationPromoter methylationSurvivalTherapeutic applicationsExpressionPatients
2016
Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells
Moreno B, Zaretsky JM, Garcia-Diaz A, Tsoi J, Parisi G, Robert L, Meeth K, Ndoye A, Bosenberg M, Weeraratna AT, Graeber TG, Comin-Anduix B, Hu-Lieskovan S, Ribas A. Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells. Cancer Immunology Research 2016, 4: 845-857. PMID: 27589875, PMCID: PMC5050168, DOI: 10.1158/2326-6066.cir-16-0060.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic AgentsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell Line, TumorDendritic CellsInterferon-gammaLymphocytes, Tumor-InfiltratingMacrophagesMelanomaMice, Inbred C57BLMutationProgrammed Cell Death 1 ReceptorProto-Oncogene Proteins B-rafXenograft Model Antitumor AssaysConceptsPD-1 blockade therapyPD-1 blockadeCD8 T cellsBlockade therapyDendritic cellsT cellsTumor modelEffector T cell functionSyngeneic murine tumor modelsAntitumor activityPD-L1 expressionT cell primingImmune cell recruitmentT cell functionTumor-associated macrophagesMurine tumor modelsTumor-host interactionsStrong antitumor activityCD80/86 costimulationL1 therapyInflammatory profileClinical benefitMHC-IIPeripheral tissuesCell recruitment
2015
Genomic Classification of Cutaneous Melanoma
Network T, Akbani R, Akdemir K, Aksoy B, Albert M, Ally A, Amin S, Arachchi H, Arora A, Auman J, Ayala B, Baboud J, Balasundaram M, Balu S, Barnabas N, Bartlett J, Bartlett P, Bastian B, Baylin S, Behera M, Belyaev D, Benz C, Bernard B, Beroukhim R, Bir N, Black A, Bodenheimer T, Boice L, Boland G, Bono R, Bootwalla M, Bosenberg M, Bowen J, Bowlby R, Bristow C, Brockway-Lunardi L, Brooks D, Brzezinski J, Bshara W, Buda E, Burns W, Butterfield Y, Button M, Calderone T, Cappellini G, Carter C, Carter S, Cherney L, Cherniack A, Chevalier A, Chin L, Cho J, Cho R, Choi Y, Chu A, Chudamani S, Cibulskis K, Ciriello G, Clarke A, Coons S, Cope L, Crain D, Curley E, Danilova L, D’Atri S, Davidsen T, Davies M, Delman K, Demchok J, Deng Q, Deribe Y, Dhalla N, Dhir R, DiCara D, Dinikin M, Dubina M, Ebrom J, Egea S, Eley G, Engel J, Eschbacher J, Fedosenko K, Felau I, Fennell T, Ferguson M, Fisher S, Flaherty K, Frazer S, Frick J, Fulidou V, Gabriel S, Gao J, Gardner J, Garraway L, Gastier-Foster J, Gaudioso C, Gehlenborg N, Genovese G, Gerken M, Gershenwald J, Getz G, Gomez-Fernandez C, Gribbin T, Grimsby J, Gross B, Guin R, Gutschner T, Hadjipanayis A, Halaban R, Hanf B, Haussler D, Haydu L, Hayes D, Hayward N, Heiman D, Herbert L, Herman J, Hersey P, Hoadley K, Hodis E, Holt R, Hoon D, Hoppough S, Hoyle A, Huang F, Huang M, Huang S, Hutter C, Ibbs M, Iype L, Jacobsen A, Jakrot V, Janning A, Jeck W, Jefferys S, Jensen M, Jones C, Jones S, Ju Z, Kakavand H, Kang H, Kefford R, Khuri F, Kim J, Kirkwood J, Klode J, Korkut A, Korski K, Krauthammer M, Kucherlapati R, Kwong L, Kycler W, Ladanyi M, Lai P, Laird P, Lander E, Lawrence M, Lazar A, Łaźniak R, Lee D, Lee J, Lee J, Lee K, Lee S, Lee W, Leporowska E, Leraas K, Li H, Lichtenberg T, Lichtenstein L, Lin P, Ling S, Liu J, Liu O, Liu W, Long G, Lu Y, Ma, Ma Y, Mackiewicz A, Mahadeshwar H, Malke J, Mallery D, Manikhas G, Mann G, Marra M, Matejka B, Mayo M, Mehrabi S, Meng S, Meyerson M, Mieczkowski P, Miller J, Miller M, Mills G, Moiseenko F, Moore R, Morris S, Morrison C, Morton D, Moschos S, Mose L, Muller F, Mungall A, Murawa D, Murawa P, Murray B, Nezi L, Ng S, Nicholson D, Noble M, Osunkoya A, Owonikoko T, Ozenberger B, Pagani E, Paklina O, Pantazi A, Parfenov M, Parfitt J, Park P, Park W, Parker J, Passarelli F, Penny R, Perou C, Pihl T, Potapova O, Prieto V, Protopopov A, Quinn M, Radenbaugh A, Rai K, Ramalingam S, Raman A, Ramirez N, Ramirez R, Rao U, Rathmell W, Ren X, Reynolds S, Roach J, Robertson A, Ross M, Roszik J, Russo G, Saksena G, Saller C, Samuels Y, Sander C, Sander C, Sandusky G, Santoso N, Saul M, Saw R, Schadendorf D, Schein J, Schultz N, Schumacher S, Schwallier C, Scolyer R, Seidman J, Sekhar P, Sekhon H, Senbabaoglu Y, Seth S, Shannon K, Sharpe S, Sharpless N, Shaw K, Shelton C, Shelton T, Shen R, Sheth M, Shi Y, Shiau C, Shmulevich I, Sica G, Simons J, Sinha R, Sipahimalani P, Sofia H, Soloway M, Song X, Sougnez C, Spillane A, Spychała A, Stretch J, Stuart J, Suchorska W, Sucker A, Sumer S, Sun Y, Synott M, Tabak B, Tabler T, Tam A, Tan D, Tang J, Tarnuzzer R, Tarvin K, Tatka H, Taylor B, Teresiak M, Thiessen N, Thompson J, Thorne L, Thorsson V, Trent J, Triche T, Tsai K, Tsou P, Van Den Berg D, Van Allen E, Veluvolu U, Verhaak R, Voet D, Voronina O, Walter V, Walton J, Wan Y, Wang Y, Wang Z, Waring S, Watson I, Weinhold N, Weinstein J, Weisenberger D, White P, Wilkerson M, Wilmott J, Wise L, Wiznerowicz M, Woodman S, Wu C, Wu C, Wu J, Wu Y, Xi R, Xu A, Yang D, Yang L, Yang L, Zack T, Zenklusen J, Zhang H, Zhang J, Zhang W, Zhao X, Zhu J, Zhu K, Zimmer L, Zmuda E, Zou L. Genomic Classification of Cutaneous Melanoma. Cell 2015, 161: 1681-1696. PMID: 26091043, PMCID: PMC4580370, DOI: 10.1016/j.cell.2015.05.044.Peer-Reviewed Original ResearchConceptsGenomic classificationProtein-based analysesComplex structural rearrangementsImmune gene expressionMutant RASGene expressionIntegrative analysisFocal amplificationGenomic alterationsStructural rearrangementsProtein expressionMutant BRAFCell markersExpressionGenesRNADNAMutationsCutaneous melanomaKIT mutationsNF1RASRearrangementEnrichmentLandscape
2009
BrafV600E cooperates with Pten loss to induce metastatic melanoma
Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky Jr W, You MJ, DePinho RA, McMahon M, Bosenberg M. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nature Genetics 2009, 41: 544-552. PMID: 19282848, PMCID: PMC2705918, DOI: 10.1038/ng.356.Peer-Reviewed Original Research