2024
Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction
Li X, Liu T, Bacchiocchi A, Li M, Cheng W, Wittkop T, Mendez F, Wang Y, Tang P, Yao Q, Bosenberg M, Sznol M, Yan Q, Faham M, Weng L, Halaban R, Jin H, Hu Z. Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction. EMBO Molecular Medicine 2024, 16: 2188-2209. PMID: 39164471, PMCID: PMC11393307, DOI: 10.1038/s44321-024-00115-0.Peer-Reviewed Original ResearchMolecular residual diseaseCirculating tumor DNAWhole-genome sequencingCell-free DNAGenome sequenceDetection of molecular residual diseaseCirculating tumor DNA detectionResidual disease detectionConsistent with clinical outcomesVariant allele frequencyResidual diseaseMelanoma patientsMonitoring immunotherapyTumor DNAEsophageal cancerClinical outcomesColorectal cancerWGS technologiesAllele frequenciesCancerDNAAnalytical sensitivitySequenceImmunotherapyRelapseEnhanced intratumoral delivery of immunomodulator MPLA via hyperbranched polyglycerol-coated biodegradable nanoparticles
Chang J, Shin K, Lewis J, Suh H, Lee J, Damsky W, Xu S, Bosenberg M, Saltzman W, Girardi M. Enhanced intratumoral delivery of immunomodulator MPLA via hyperbranched polyglycerol-coated biodegradable nanoparticles. Journal Of Investigative Dermatology 2024 PMID: 39122142, DOI: 10.1016/j.jid.2024.07.019.Peer-Reviewed Original ResearchMonophosphoryl lipid ATumor microenvironmentImmunomodulatory agentsStimulation of anti-tumor immune responseEfficacy of monophosphoryl lipid AT-helper (Th)1 responsesAnti-tumor immune responseTumor-draining lymph nodesToxicity associated with systemic administrationImmune responseModel of malignant melanomaAgonist monophosphoryl lipid ABiodegradable nanoparticlesImmunogenic tumor microenvironmentAntitumor immune responseDraining lymph nodesSystemic side effectsNatural killer cellsGradual drug releaseKiller cellsAntitumor efficacyMalignant melanomaImproved survivalLymph nodesChemotherapeutic agentsDevelopment of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC)
Kashima S, Gupta R, Moritz V, Sadak K, Adeniran A, Humphrey P, Dinulescu D, Palmer D, Hammond S, Bosenberg M, Hurwitz M, Kenney P, Braun D. Development of anex vivo patient-derived tumor model (PDTM) to assess the tumor microenvironment in renal cell carcinoma (RCC). The Oncologist 2024, 29: s5-s6. PMCID: PMC11301923, DOI: 10.1093/oncolo/oyae181.008.Peer-Reviewed Original ResearchRCC tumor microenvironmentPatient-derived tumor modelsRenal cell carcinomaImmune checkpoint inhibitorsT cell functionPeripheral blood mononuclear cellsEnzyme-linked immunosorbent assayTumor microenvironmentT cellsFlow cytometryTumor fragmentsIFN-gTumor modelTumor samplesCytokine productionHealthy donor peripheral blood mononuclear cellsImpact of immune checkpoint inhibitorsAnti-PD-1 monoclonal antibodyDonor peripheral blood mononuclear cellsCD4+CD25+ regulatory T cellsCD8+ T cell populationsResection of renal cell carcinomaSurgical resection of renal cell carcinomaAnti-PD-1 antibodyMetastatic renal cell carcinoma
2023
1025 Tumor-specific CD8+ T cells epigenetically licensed by IL-7R are critical for anti-tumor immunity in melanoma
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. 1025 Tumor-specific CD8+ T cells epigenetically licensed by IL-7R are critical for anti-tumor immunity in melanoma. 2023, a1133-a1133. DOI: 10.1136/jitc-2023-sitc2023.1025.Peer-Reviewed Original ResearchManipulating 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 killingExpressionCombinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance.
Krykbaeva I, Bridges K, Damsky W, Pizzurro G, Alexander A, McGeary M, Park K, Muthusamy V, Eyles J, Luheshi N, Turner N, Weiss S, Olino K, Kaech S, Kluger H, Miller-Jensen K, Bosenberg M. Combinatorial Immunotherapy with Agonistic CD40 Activates Dendritic Cells to Express IL12 and Overcomes PD-1 Resistance. Cancer Immunology Research 2023, 11: 1332-1350. PMID: 37478171, DOI: 10.1158/2326-6066.cir-22-0699.Peer-Reviewed Original ResearchConceptsPD-1 resistanceDendritic cellsTumor regressionAnti-PD-1 resistanceActivates Dendritic CellsCytokine secretion profilingSystemic cytokine profileTriple therapy combinationInnate immune activationAdaptive immune responsesComplete tumor regressionMajority of miceSignificant clinical challengeMouse melanoma modelT cell activationAgonistic CD40Checkpoint inhibitorsDC subsetsTriple therapyCytokine profileImmune activationCombinatorial immunotherapyTherapy combinationsT cellsClinical challengeIL-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 analysisCooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity
Lei Y, VanPortfliet J, Chen Y, Bryant J, Li Y, Fails D, Torres-Odio S, Ragan K, Deng J, Mohan A, Wang B, Brahms O, Yates S, Spencer M, Tong C, Bosenberg M, West L, Shadel G, Shutt T, Upton J, Li P, West A. Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity. Cell 2023, 186: 3013-3032.e22. PMID: 37352855, PMCID: PMC10330843, DOI: 10.1016/j.cell.2023.05.039.Peer-Reviewed Original ResearchMouse models for immuno-oncology
Bosenberg M, Liu E, Yu C, Palucka K. Mouse models for immuno-oncology. Trends In Cancer 2023, 9: 578-590. PMID: 37087398, DOI: 10.1016/j.trecan.2023.03.009.Peer-Reviewed Original ResearchDiscovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations
Yan H, Talty R, Jain A, Cai Y, Zheng J, Shen X, Muca E, Paty P, Bosenberg M, Khan S, Johnson C. Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations. Redox Biology 2023, 62: 102699. PMID: 37086630, PMCID: PMC10172914, DOI: 10.1016/j.redox.2023.102699.Peer-Reviewed Original ResearchConceptsKRAS mutant tumorsMale CRC patientsCRC patientsMale patientsKRAS mutationsMutant tumorsOverall survivalMale colorectal cancer patientsKRAS wild-type tumorsAberrant tumor metabolismColorectal cancer patientsCRC patient cohortsColorectal cancer casesFerroptosis-related genesWild-type tumorsNovel potential avenuesNormal colon tissuesPoor OSKRAS statusAdverse outcomesCRC cellsPatient cohortCancer patientsType tumorsCancer casesInterMEL: 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 rateType 2 Dendritic Cells Orchestrate a Local Immune Circuit to Confer Antimetastatic Immunity
Weizman O, Luyten S, Krykbaeva I, Song E, Mao T, Bosenberg M, Iwasaki A. Type 2 Dendritic Cells Orchestrate a Local Immune Circuit to Confer Antimetastatic Immunity. The Journal Of Immunology 2023, 210: 1146-1155. PMID: 36881866, PMCID: PMC10067787, DOI: 10.4049/jimmunol.2200697.Peer-Reviewed Original ResearchConceptsType 2 dendritic cellsMetastatic burdenImmune circuitsDendritic cellsConventional type 2 dendritic cellsSyngeneic murine melanomaNK cell compartmentImmune cell responsesColon cancer modelEarly metastatic seedingMetastatic controlTranscription factor IRF3DC populationsNK cellsProinflammatory cytokinesNucleic acid sensingPrimary tumorEffector responsesMetastatic spreadDisease outcomeIntracardiac injectionT cellsInitial immunityTissue-specific ablationCancer modelValidation 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 protocolFerroptosis in colorectal cancer: a future target?
Yan H, Talty R, Aladelokun O, Bosenberg M, Johnson C. Ferroptosis in colorectal cancer: a future target? British Journal Of Cancer 2023, 128: 1439-1451. PMID: 36703079, PMCID: PMC10070248, DOI: 10.1038/s41416-023-02149-6.Peer-Reviewed Original ResearchConceptsColorectal cancerRegulated cell deathCurrent treatment optionsForms of RCDCancer deathTreatment optionsCRC therapyCancer recurrenceTreatment strategiesRadiation therapyOvert toxicityTherapeutic targetDrug resistanceTherapyCancer cellsFerroptosisPotential roleCancerCell deathFuture targetsDeathRecent studiesBiological pathwaysChemotherapySurgeryPTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6
Yu Y, Dai M, Huang L, Chen W, Yu E, Mendoza A, Michael H, Khanna C, Bosenberg M, McMahon M, Merlino G. PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6. IScience 2023, 26: 106070. PMID: 36824269, PMCID: PMC9942123, DOI: 10.1016/j.isci.2023.106070.Peer-Reviewed Original ResearchProtein phosphatase activityPhosphatase activityPTEN protein phosphatase activityER stress sensor ATF6ER stressPTEN phosphatase activityPTEN expressionMelanoma cell invasivenessNovel candidate therapeutic targetInhibits metastasisIGF1R pathwayIGF1R levelsHuman melanoma samplesTumor suppressorCandidate therapeutic targetCell invasivenessATF6Melanoma samplesMetastatic progressionTherapeutic targetExpressionDose-dependent mannerPathwayMouse melanoma modelMutant melanoma
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 therapyTherapyIsotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity
Zhang X, Halberstam A, Zhu W, Leitner B, Thakral D, Bosenberg M, Perry R. Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity. Cancer & Metabolism 2022, 10: 21. PMID: 36457136, PMCID: PMC9714036, DOI: 10.1186/s40170-022-00296-7.Peer-Reviewed Original ResearchTumor microenvironmentAnti-tumor immunityPotential prognostic factorsObesity-associated cancersPotential prognostic predictorPatient RNA-seq dataSubset of studiesImmunogenic tumorsCancer Genome AtlasLymphocyte infiltrationMelanoma cell linesPrognostic factorsPrognostic predictorMetabolic therapyMelanoma subtypesMurine modelImmune functionMetabolic gene expressionMelanoma progressionMelanomaSubstrate metabolismMetabolic flux studiesGene expressionGenome AtlasCell linesThe Crossroads of Cancer Epigenetics and Immune Checkpoint Therapy.
Micevic G, Bosenberg M, Yan Q. The Crossroads of Cancer Epigenetics and Immune Checkpoint Therapy. Clinical Cancer Research 2022, 29: 1173-1182. PMID: 36449280, PMCID: PMC10073242, DOI: 10.1158/1078-0432.ccr-22-0784.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsImmune checkpoint inhibitorsImmune checkpoint therapyT cell exhaustionCheckpoint therapyAntitumor immune responseT cell populationsCell-intrinsic immunityTypes of cancerViral mimicry responseLow response rateCheckpoint inhibitorsCurrent immunotherapiesPancreatic cancerSustained responsePreclinical modelsTreatment outcomesImmune responseEndogenous antigensResponse rateTumor typesMultiple epigenetic regulatorsCritical mediatorLow immunogenicityTherapyCancer