2023
IL-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 mice
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 applicationsExpressionPatientsInhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer
Theodosakis N, Langdon CG, Micevic G, Krykbaeva I, Means RE, Stern DF, Bosenberg MW. Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer. Pigment Cell & Melanoma Research 2018, 32: 292-302. PMID: 30281931, PMCID: PMC6590911, DOI: 10.1111/pcmr.12742.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationColorectal NeoplasmsDrug Resistance, NeoplasmDrug SynergismHumansHydroxymethylglutaryl-CoA Reductase InhibitorsLung NeoplasmsMaleMelanomaMevalonic AcidMice, NudeMitogen-Activated Protein KinasesPrenylationProtein Kinase InhibitorsProtein Processing, Post-TranslationalSignal TransductionConceptsUseful adjunctive therapyHMG-CoA reductase inhibitorsAnti-tumor effectsAdjunctive therapyInhibition of isoprenylationLung cancerMEK inhibitionReductase inhibitorsMAPK blockadeDriver mutationsAdditional studiesStatinsTherapyMelanomaTumorsVemurafenibMAPK pathwayDownstream metabolitesInhibitionMAPKAdjunctiveColorectalSelumetinibBlockadeCancer
2017
UV‐induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model
Wang J, Perry CJ, Meeth K, Thakral D, Damsky W, Micevic G, Kaech S, Blenman K, Bosenberg M. UV‐induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model. Pigment Cell & Melanoma Research 2017, 30: 428-435. PMID: 28379630, PMCID: PMC5820096, DOI: 10.1111/pcmr.12591.Peer-Reviewed Original ResearchConceptsHigh somatic mutation burdenSomatic mutation burdenT cellsMutation burdenAnti-PD-1 therapyFunctional T cell responsesImmune checkpoint inhibitionAntitumor immune responseCD8 T cellsT cell responsesMouse melanoma modelCell numberSomatic mutationsMouse melanoma cell lineMelanoma cell linesTumor challengeAntitumor responseCheckpoint inhibitionImmune responseMelanoma modelHigh dosesImmune systemCell responsesMelanomas exhibitTumorsp90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis
Theodosakis N, Micevic G, Langdon CG, Ventura A, Means R, Stern DF, Bosenberg MW. p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis. Journal Of Investigative Dermatology 2017, 137: 2187-2196. PMID: 28599981, PMCID: PMC6342201, DOI: 10.1016/j.jid.2016.12.033.Peer-Reviewed Original ResearchConceptsProtein synthesisRibosomal S6 kinase (RSK) familyPatient-derived melanoma cell linesDifferential protein expressionReverse phase protein arrayPhase protein arrayTranslation complexesKinase familyBI-D1870RSK inhibitorsMelanoma cell linesProtein arraysCell proliferationInhibitor treatmentProtein expressionCell linesNew targetsHuman melanoma patientsBRAF inhibitor vemurafenibAberrant DNA methylation in melanoma: biomarker and therapeutic opportunities
Micevic G, Theodosakis N, Bosenberg M. Aberrant DNA methylation in melanoma: biomarker and therapeutic opportunities. Clinical Epigenetics 2017, 9: 34. PMID: 28396701, PMCID: PMC5381063, DOI: 10.1186/s13148-017-0332-8.Peer-Reviewed Original ResearchConceptsAberrant DNA methylationDNA methylationMethylation changesDNA methylation changesEpigenetic hallmarkMelanoma formationMethylation signaturesMethylationImportant unresolved questionsBiomarker opportunitiesTherapeutic opportunitiesTherapeutic developmentMethylation methodUnresolved questionsTherapeutic potentialImportant roleRecent advancesPotential biomarkersGenesRecent developmentsHallmarkConsiderable effortDevelopmentBiomarkersAdvancesAttenuation of genome-wide 5-methylcytosine level is an epigenetic feature of cutaneous malignant melanomas
Micevic G, Theodosakis N, Taube JM, Bosenberg MW, Rodi N. Attenuation of genome-wide 5-methylcytosine level is an epigenetic feature of cutaneous malignant melanomas. Melanoma Research 2017, 27: 85-96. PMID: 27997431, PMCID: PMC5812886, DOI: 10.1097/cmr.0000000000000315.Peer-Reviewed Original ResearchConceptsS-adenosyl methionineMelanoma cell linesEpigenetic featuresCell linesInactive chromatin regionsGenome-wide increaseUniversal methyl group donorMethyl group donorChromatin regionsCancer epigenomeEpigenetic modificationsEpigenetic abnormalitiesCytosine residuesMelanoma cell growthEpigenome modulationMalignant melanomaCell growthCovalent changesGroup donorSubcytotoxic levelsChemical substratesMelanoma cellsCutaneous malignant melanomaDose-dependent increaseResidues
2016
Cell and Tissue Display
Theodosakis N, Micevic G, Bosenberg MW, Rodić N. Cell and Tissue Display. Journal Of Histochemistry & Cytochemistry 2016, 64: 403-411. PMID: 27270967, PMCID: PMC4931762, DOI: 10.1369/0022155416651065.Peer-Reviewed Original ResearchIntegrative discovery of CD98 as a melanoma biomarker
Theodosakis N, Micevic G, Sharma R, Baras AS, Lazova R, Bosenberg MW, Rodić N. Integrative discovery of CD98 as a melanoma biomarker. Pigment Cell & Melanoma Research 2016, 29: 385-387. PMID: 26850337, DOI: 10.1111/pcmr.12464.Peer-Reviewed Original Research
2015
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses
Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell 2015, 162: 1217-1228. PMID: 26321681, PMCID: PMC4567953, DOI: 10.1016/j.cell.2015.08.012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalciumCD4-Positive T-LymphocytesEndoplasmic ReticulumGlycolysisHexokinaseImmunotherapyLymphocytes, Tumor-InfiltratingMelanomaMiceMonitoring, ImmunologicNFATC Transcription FactorsPhosphoenolpyruvateReceptors, Antigen, T-CellSarcoplasmic Reticulum Calcium-Transporting ATPasesSignal TransductionTransforming Growth Factor betaTumor MicroenvironmentConceptsAnti-tumor T cell responsesT cell responsesT cellsEffector functionsCell responsesTumor-reactive T cellsTumor-infiltrating T cellsPhosphoenolpyruvate carboxykinase 1Tumoricidal effector functionsTumor-specific CD4CD8 T cellsT cell activityMelanoma-bearing miceAerobic glycolysisActivated T cellsMetabolic checkpointTumor growthCell activityTumor microenvironmentNFAT SignalingMetabolic reprogrammingCarboxykinase 1Anabolic metabolismCellsATPase activityBRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume
Theodosakis N, Held MA, Marzuka-Alcala A, Meeth KM, Micevic G, Long GV, Scolyer RA, Stern DF, Bosenberg MW. BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume. Molecular Cancer Therapeutics 2015, 14: 1680-1692. PMID: 25948295, PMCID: PMC4497841, DOI: 10.1158/1535-7163.mct-15-0080.Peer-Reviewed Original ResearchConceptsGlucose uptakeWeeks of treatmentBRAF kinase inhibitorsHigh response rateTumor cell deathMetastatic diseaseTransmembrane glucose transportMetastatic melanomaPatient cohortCellular glucose uptakeRadiographic changesVemurafenib treatmentBRAF inhibitorsBRAF inhibitionResponse rateEmission tomographyPhysiologic parametersNew protein translationKinase inhibitorsEarly responseImportant physiologic parametersCell volumeMelanomaVolume reductionCell volume regulation
2014
Mitochondrial function in melanoma
Theodosakis N, Micevic G, Kelly DP, Bosenberg M. Mitochondrial function in melanoma. Archives Of Biochemistry And Biophysics 2014, 563: 56-59. PMID: 24997363, DOI: 10.1016/j.abb.2014.06.028.Peer-Reviewed Original Research