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
2024
Setdb1-loss induces type-I interferons and immune clearance of melanoma.
McGeary M, Damsky W, Daniels A, Lang S, Xu Q, Song E, Huet-Calderwood C, Lou H, Paradkar S, Micevic G, Kaech S, Calderwood D, Turk B, Yan Q, Iwasaki A, Bosenberg M. Setdb1-loss induces type-I interferons and immune clearance of melanoma. Cancer Immunology Research 2024 PMID: 39589394, DOI: 10.1158/2326-6066.cir-23-0514.Peer-Reviewed Original ResearchT cell infiltrationMHC-I expressionType I interferonImmune clearanceCD8+ T cell-dependent mannerIncreased CD8+ T cell infiltrationCD8+ T cell infiltrationDecreased MHC-I expressionAnti-cancer immune responseT cell-dependent mannerCD8+ T cellsDecreased T-cell infiltrationComplete tumor clearanceImmunity to melanomaIncreased melanoma growthInflamed tumor microenvironmentLoss of SETDB1Type I interferon receptorTreatment of melanomaType I interferon signalingWhole-genome CRISPR screenEndogenous retrovirusesType I interferon expressionMetastatic diseaseTumor clearanceEnhanced 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 agents
2023
Combinatorial 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 challenge
2020
IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy
Zhou T, Damsky W, Weizman OE, McGeary MK, Hartmann KP, Rosen CE, Fischer S, Jackson R, Flavell RA, Wang J, Sanmamed MF, Bosenberg MW, Ring AM. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 2020, 583: 609-614. PMID: 32581358, PMCID: PMC7381364, DOI: 10.1038/s41586-020-2422-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD8-Positive T-LymphocytesDisease Models, AnimalFemaleHepatocyte Nuclear Factor 1-alphaHistocompatibility Antigens Class IHumansImmunotherapyIntercellular Signaling Peptides and ProteinsInterleukin-18Kaplan-Meier EstimateKiller Cells, NaturalLymphocytes, Tumor-InfiltratingMaleMiceNeoplasmsReceptors, Interleukin-18Stem CellsTumor MicroenvironmentConceptsIL-18IL-18BPT cellsAnti-PD-1 resistant tumorsWild-type IL-18Potent anti-tumor effectsMajor histocompatibility complex class IIL-18 pathwayIL-18 therapyInterleukin-18 pathwayMajor therapeutic barrierStem-like TCF1Anti-tumor immunityTumor-infiltrating lymphocytesNatural killer cellsRecombinant IL-18Histocompatibility complex class IAnti-tumor effectsComplex class IAnti-tumor activityMouse tumor modelsModern immunotherapyPrecursor CD8Effector CD8Exhausted CD8
2019
LB1122 Myeloid targeting in combination with PD1 inhibition boosts anti-tumor immunity in melanoma
Krykbaeva I, Damsky W, Turner N, Perry C, Kluger H, Bosenberg M. LB1122 Myeloid targeting in combination with PD1 inhibition boosts anti-tumor immunity in melanoma. Journal Of Investigative Dermatology 2019, 139: b19. DOI: 10.1016/j.jid.2019.06.089.Peer-Reviewed Original ResearchEvaluating the role of the COX2/PGE2 pathway in anti-melanoma immunity.
Ferreira M, Krykbaeva I, Damsky W, Kluger H, Bosenberg M. Evaluating the role of the COX2/PGE2 pathway in anti-melanoma immunity. Journal Of Clinical Oncology 2019, 37: e14114-e14114. DOI: 10.1200/jco.2019.37.15_suppl.e14114.Peer-Reviewed Original ResearchC57BL6/J micePD-L1 upregulationT cell exhaustionTumor implantationJ miceCell exhaustionDay 7Male C57BL6/J miceCOX2/PGE2 pathwayDay 32Anti-melanoma immunityBreast cancer modelSafety of inhibitorsAttractive pharmacologic targetML/daySyngeneic cell linesCheckpoint inhibitorsPartial responseMelanoma patientsComplete regressionSafety profileMetastatic melanomaPathway blockadePGE2 pathwayCOX2 inhibitors783 Evaluating the impact of high-dose steroids on checkpoint inhibitor efficacy in a murine model of melanoma
Ferreira M, Damsky W, Bosenberg M. 783 Evaluating the impact of high-dose steroids on checkpoint inhibitor efficacy in a murine model of melanoma. Journal Of Investigative Dermatology 2019, 139: s135. DOI: 10.1016/j.jid.2019.03.859.Peer-Reviewed Original Research789 Immune checkpoint therapy polarizes fibroblasts into a proinflammatory state
Ramseier J, Thakral D, Damsky W, Bosenberg M. 789 Immune checkpoint therapy polarizes fibroblasts into a proinflammatory state. Journal Of Investigative Dermatology 2019, 139: s136. DOI: 10.1016/j.jid.2019.03.865.Peer-Reviewed Original Research
2018
1245 PD-1 blockade impedes tumor growth in the immunogenic YUMMER1.7 mouse melanoma model
Turner N, Damsky W, Wang J, Meeth K, Blenman K, Bosenberg M. 1245 PD-1 blockade impedes tumor growth in the immunogenic YUMMER1.7 mouse melanoma model. Journal Of Investigative Dermatology 2018, 138: s211. DOI: 10.1016/j.jid.2018.03.1260.Peer-Reviewed Original Research
2017
766 Exposure to ultraviolet light enhances anti-tumor immunity and response to immunotherapy in a mouse model of melanoma
Damsky W, Wang J, Perry C, Meeth K, Kaech S, Bosenberg M. 766 Exposure to ultraviolet light enhances anti-tumor immunity and response to immunotherapy in a mouse model of melanoma. Journal Of Investigative Dermatology 2017, 137: s132. DOI: 10.1016/j.jid.2017.02.791.Peer-Reviewed Original Research
2016
A comprehensive system of congenic mouse melanoma models for evaluation of immune therapies
Bosenberg M, Meeth K, Damsky W. A comprehensive system of congenic mouse melanoma models for evaluation of immune therapies. The Journal Of Immunology 2016, 196: 144.19-144.19. DOI: 10.4049/jimmunol.196.supp.144.19.Peer-Reviewed Original ResearchImmune therapyMouse modelImmune systemImmune checkpoint inhibitorsSubset of patientsRenal cell carcinomaMouse melanoma modelMouse melanoma cell lineCheckpoint inhibitorsMelanoma cell linesMelanoma patientsCell carcinomaLung cancerCancer immunologyMalignant melanomaProstate cancerTherapeutic approachesMelanoma modelSkin cancerHuman melanomaTherapyTumor microenvironmentCancerFlow cytometryPatients
2015
mTORC1 Activation Blocks Braf V600E -Induced Growth Arrest but Is Insufficient for Melanoma Formation
Damsky W, Micevic G, Meeth K, Muthusamy V, Curley DP, Santhanakrishnan M, Erdelyi I, Platt JT, Huang L, Theodosakis N, Zaidi MR, Tighe S, Davies MA, Dankort D, McMahon M, Merlino G, Bardeesy N, Bosenberg M. mTORC1 Activation Blocks Braf V600E -Induced Growth Arrest but Is Insufficient for Melanoma Formation. Cancer Cell 2015, 27: 41-56. PMID: 25584893, PMCID: PMC4295062, DOI: 10.1016/j.ccell.2014.11.014.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsCell Line, TumorCell ProliferationCyclin-Dependent Kinase Inhibitor p16HumansMechanistic Target of Rapamycin Complex 1Mechanistic Target of Rapamycin Complex 2MelanocytesMelanoma, ExperimentalMiceMicroRNAsMolecular Sequence DataMultiprotein ComplexesMutationNevusProtein Serine-Threonine KinasesProto-Oncogene Proteins B-rafSignal TransductionSkin NeoplasmsTOR Serine-Threonine KinasesConceptsMelanoma formationGrowth arrestStable growth arrestMTORC2/AktSTK11 lossCDKN2A lossAkt activationIGF1R signalingMice resultsActivationArrestMTORC2Nevus developmentMTORC1/2SignalingAktMelanocytic nevus developmentMelanomagenesisMTORProgressionCDKN2AMelanocytesInactivationUpregulationComplete progression
2011
β-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas
Damsky WE, Curley DP, Santhanakrishnan M, Rosenbaum LE, Platt JT, Rothberg BE, Taketo MM, Dankort D, Rimm DL, McMahon M, Bosenberg M. β-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas. Cancer Cell 2011, 20: 741-754. PMID: 22172720, PMCID: PMC3241928, DOI: 10.1016/j.ccr.2011.10.030.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, DifferentiationBenzamidesBeta CateninCell Transformation, NeoplasticColorectal NeoplasmsEnzyme ActivationGene Knockdown TechniquesHumansImatinib MesylateKaplan-Meier EstimateLung NeoplasmsLymphatic MetastasisMelanocytesMelanoma, ExperimentalMiceMice, 129 StrainMice, Inbred C57BLMice, TransgenicPhosphorylationPiperazinesProtein StabilityProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-aktPTEN PhosphohydrolasePyrimidinesSignal TransductionSkin NeoplasmsSplenic NeoplasmsTranscription, GeneticTumor Cells, CulturedConceptsΒ-catenin levelsPI3K/AktLymph nodesMetastatic tumorsFrequent metastasisTumor differentiationMalignant melanomaMAPK/ERKMelanoma metastasesMouse modelControl metastasisHuman melanomaMelanomaMetastasisΒ-catenin stabilizationPTEN lossCentral mediatorMetastasis regulatorsΒ-cateninSpecific changesFunctional implicationsWntLung