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 clearanceHypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Robles-Oteíza C, Hastings K, Choi J, Sirois I, Ravi A, Expósito F, de Miguel F, Knight J, López-Giráldez F, Choi H, Socci N, Merghoub T, Awad M, Getz G, Gainor J, Hellmann M, Caron É, Kaech S, Politi K. Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer. Journal Of Experimental Medicine 2024, 222: e20231106. PMID: 39585348, DOI: 10.1084/jem.20231106.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsNon-small cell lung cancerAcquired resistanceCheckpoint inhibitorsResistant tumorsPatients treated with anti-PD-1/PD-L1 therapyAnti-PD-1/PD-L1 therapyLung cancerResistance to immune checkpoint inhibitorsAssociated with decreased progression-free survivalHypoxia activated pro-drugsTargeting hypoxic tumor regionsTreat non-small cell lung cancerAnti-CTLA-4Anti-PD-1Immune checkpoint inhibitionTumor metabolic featuresProgression-free survivalCell lung cancerResistant cancer cellsHypoxic tumor regionsMHC-II levelsRegions of hypoxiaKnock-outCheckpoint inhibitionScavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling.
Xu Z, Kuhlmann-Hogan A, Xu S, Tseng H, Chen D, Tan S, Sun M, Tripple V, Bosenberg M, Miller-Jensen K, Kaech S. Scavenger Receptor CD36 in Tumor-Associated Macrophages Promotes Cancer Progression by Dampening Type I Interferon Signaling. Cancer Research 2024 PMID: 39546763, DOI: 10.1158/0008-5472.can-23-4027.Peer-Reviewed Original ResearchTumor-associated macrophagesIFN-ITumor microenvironmentTumor growthHeterogeneous population of myeloid cellsPharmacological inhibition of CD36Population of myeloid cellsTumor cell quiescenceAnti-tumor immunityDelayed tumor growthTumor inflammatory microenvironmentElevated type I interferonReduced tumor growthMyeloid-specific deletionDeletion of CD36Type I interferon signalingInhibition of CD36Promote cancer progressionI interferon signalingIFN-I responseIFN-I signalingType I interferonScavenger receptor CD36TAM functionNatural suppressorTranscriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors
McGuire C, Meehan A, Couser E, Bull L, Minor A, Kuhlmann-Hogan A, Kaech S, Shaw R, Eichner L. Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2317694121. PMID: 39388266, PMCID: PMC11494357, DOI: 10.1073/pnas.2317694121.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesCell Line, TumorChemokine CXCL10Gene Expression Regulation, NeoplasticHistone Deacetylase InhibitorsHistone DeacetylasesHumansLung NeoplasmsMiceMutationProto-Oncogene Proteins p21(ras)PyridinesPyridonesPyrimidinonesT-LymphocytesTranscription, GeneticTumor MicroenvironmentConceptsT cell recruitmentLung tumorsHistone deacetylase 3Enhanced T cell recruitmentCombined treatmentLung tumors in vivoGenetically engineered mouse modelsT cell exclusionInhibition of histone deacetylase 3Tumor immune microenvironmentTumor growth controlKRAS mutant lung tumorsTumors in vivoLung cancer cellsImmune microenvironmentT cellsTissue-specific fashionMouse modelPathway inhibitorTumorPharmacological inhibitionCancer cellsFunction in vivoTranscriptional regulationTranscriptional repressionACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses
Kaymak I, Watson M, Oswald B, Ma S, Johnson B, DeCamp L, Mabvakure B, Luda K, H. E, Lau K, Fu Z, Muhire B, Kitchen-Goosen S, Vander Ark A, Dahabieh M, Samborska B, Vos M, Shen H, Fan Z, Roddy T, Kingsbury G, Sousa C, Krawczyk C, Williams K, Sheldon R, Kaech S, Roy D, Jones R. ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses. Journal Of Experimental Medicine 2024, 221: e20231820. PMID: 39150482, PMCID: PMC11329787, DOI: 10.1084/jem.20231820.Peer-Reviewed Original ResearchConceptsAcyl-CoA synthetase short-chain family member 2Acetyl-CoA productionATP citrate lyaseChromatin accessibilityAcetyl-CoAEnzyme ATP citrate lyaseFamily member 2Function in vivoCoordination of cellular metabolismTCA cycleMetabolic nodesGene locusCitrate lyaseT cell effector responsesHistone acetylationCellular metabolismEffector functionsCD8 T cellsResponse to infectionMember 2ChromatinEffector responsesMetabolic substratesT cell response to infectionT cellsARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity
Maxwell M, Hom-Tedla M, Yi J, Li S, Rivera S, Yu J, Burns M, McRae H, Stevenson B, Coakley K, Ho J, Gastelum K, Bell J, Jones A, Eskander R, Dykhuizen E, Shadel G, Kaech S, Hargreaves D. ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity. Cell 2024, 187: 3390-3408.e19. PMID: 38754421, PMCID: PMC11193641, DOI: 10.1016/j.cell.2024.04.025.Peer-Reviewed Original ResearchImmune checkpoint blockadeAnti-tumor immunityIncreased CD8+ T cell infiltrationCD8+ T cell infiltrationT cell infiltrationType I IFN signalingGene expression signaturesICB treatmentCheckpoint blockadeIndependent of microsatellite instabilityARID1A mutationsCytolytic activityImmune phenotypeMurine modelCell infiltrationARID1A lossClinical trialsMutant cancersARID1AHuman cancersExpression signaturesGene upregulationMicrosatellite instabilityCancerInterferonEGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.
Kuhlmann-Hogan A, Cordes T, Xu Z, Kuna R, Traina K, Robles-Oteiza C, Ayeni D, Kwong E, Levy S, Globig A, Nobari M, Cheng G, Leibel S, Homer R, Shaw R, Metallo C, Politi K, Kaech S. EGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth. Cancer Discovery 2024, 14: 524-545. PMID: 38241033, PMCID: PMC11258210, DOI: 10.1158/2159-8290.cd-23-0434.Peer-Reviewed Original ResearchLung adenocarcinomaGM-CSFEGFR-mutant lung adenocarcinomaGM-CSF secretionProinflammatory immune responseSuppress tumor progressionLocal immunosuppressionStatin therapyTherapeutic combinationsNovel therapiesTumor cellsTumor progressionTumor growthLung adenocarcinoma cellsEGFR phosphorylationImmune responseTransformed epitheliumCancer cellsInflammatory functionsEGFR signalingMacrophage metabolismAlveolar macrophagesIncreased cholesterol synthesisMetabolic supportOncogenic signalingEGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth.
Kuhlmann-Hogan A, Cordes T, Xu Z, Kuna R, Traina K, Robles-Oteíza C, Ayeni D, Kwong E, Levy S, Globig A, Nobari M, Cheng G, Leibel S, Homer R, Shaw R, Metallo C, Politi K, Kaech S. EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth. Cancer Discovery 2024, of1-of22. PMID: 38270272, DOI: 10.1158/2159-8290.cd-23-0434.Peer-Reviewed Original ResearchLung adenocarcinomaGM-CSFEGFR-mutant lung adenocarcinomaT cell-based immunotherapyTransformed epitheliumOncogenic signalingGM-CSF secretionProinflammatory immune responseSuppress tumor progressionLocal immunosuppressionStatin therapyTherapeutic combinationsNovel therapiesTumor cellsTumor progressionTumor growthLung cancerLung adenocarcinoma cellsEGFR phosphorylationImmune responseImmunological supportCancer cellsInflammatory functionsAlveolar macrophagesIncreased cholesterol synthesis
2023
Early Chromatin Remodeling Events in Acutely Stimulated CD8+ T Cells
McDonald B, Chick B, Hargreaves D, Kaech S. Early Chromatin Remodeling Events in Acutely Stimulated CD8+ T Cells. The Yale Journal Of Biology And Medicine 2023, 96: 467-473. PMID: 38161581, PMCID: PMC10751865, DOI: 10.59249/axgu7370.Peer-Reviewed Original Research1014 Adrenergic receptors regulate T cell differentiation in viral infection and cancer
Globig A, Zhao S, Roginsky J, Avina-Ochoa N, Heeg M, Chaudhary O, Hoffmann F, Chen D, O’Connor C, Emu B, Kaech S. 1014 Adrenergic receptors regulate T cell differentiation in viral infection and cancer. 2023, a1122-a1122. DOI: 10.1136/jitc-2023-sitc2023.1014.Peer-Reviewed Original Research
2020
The role of CD36 in macrophage lipid metabolism and function in tumor microenvironment
Xu Z, Xu S, Kuhlmann A, Kaech S. The role of CD36 in macrophage lipid metabolism and function in tumor microenvironment. The Journal Of Immunology 2020, 204: 240.9-240.9. DOI: 10.4049/jimmunol.204.supp.240.9.Peer-Reviewed Original ResearchTumor-associated macrophagesTumor microenvironmentPhenotype of tumor-associated macrophagesTumor-infiltrating immune populationsExpression of PD-L1Function of tumor-associated macrophagesExpression of scavenger receptor CD36Pro-tumor phenotypeLevels of F4/80Mouse melanoma modelMyeloid-specific deficiencyAnti-tumor functionPro-tumor functionsLipid metabolic phenotypesLipid metabolismSingle-cell RNA sequencingExpression of CD36Scavenger receptor CD36TAM subsetsPD-L1Immunosuppressive phenotypeUptake of oxLDLMacrophage lipid metabolismMelanoma modelUptake of oxidized LDL
2014
The Transcription Factor FoxO1 Sustains Expression of the Inhibitory Receptor PD-1 and Survival of Antiviral CD8+ T Cells during Chronic Infection
Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM. The Transcription Factor FoxO1 Sustains Expression of the Inhibitory Receptor PD-1 and Survival of Antiviral CD8+ T Cells during Chronic Infection. Immunity 2014, 41: 802-814. PMID: 25464856, PMCID: PMC4270830, DOI: 10.1016/j.immuni.2014.10.013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, BlockingAntibodies, MonoclonalCD28 AntigensCD8-Positive T-LymphocytesCell DifferentiationCell Line, TumorChronic DiseaseForkhead Box Protein O1Forkhead Transcription FactorsGranzymesHumansInterferon-gammaJurkat CellsLymphocyte ActivationLymphocytic ChoriomeningitisLymphocytic choriomeningitis virusMiceMice, Inbred C57BLMice, TransgenicProgrammed Cell Death 1 ReceptorProto-Oncogene Proteins c-aktReceptors, Antigen, T-CellSirolimusT-Lymphocytes, CytotoxicTOR Serine-Threonine KinasesConceptsChronic viral infectionsVirus-specific CTLPD-1Viral infectionMurine lymphocytic choriomeningitis virus infectionInhibitory receptor PD-1Lymphocytic choriomeningitis virus infectionCell death protein 1Receptor PD-1Death protein 1MTOR inhibitor rapamycinExhausted CTLsAntiviral CD8Activation of AktInhibitory receptorsTranscription factor FOXO1Chronic infectionT cellsT lymphocytesTherapeutic effectVirus infectionPersistent infectionPositive feedback pathwayInfectionCTLCD4+ T Cell Help Guides Formation of CD103+ Lung-Resident Memory CD8+ T Cells during Influenza Viral Infection
Laidlaw BJ, Zhang N, Marshall HD, Staron MM, Guan T, Hu Y, Cauley LS, Craft J, Kaech SM. CD4+ T Cell Help Guides Formation of CD103+ Lung-Resident Memory CD8+ T Cells during Influenza Viral Infection. Immunity 2014, 41: 633-645. PMID: 25308332, PMCID: PMC4324721, DOI: 10.1016/j.immuni.2014.09.007.Peer-Reviewed Original ResearchConceptsT cellsTRM cellsT-betTissue-resident memory T cellsLung-resident memory CD8T cell-dependent signalsT cell-derived interferonTranscription factor T-betLung Trm cellsMemory T cellsInfluenza viral infectionInfluenza virus infectionT cell helpHeterosubtypic challengeCD103 expressionMemory CD8Respiratory infectionsMucosal sitesCell helpAirway epitheliumVirus infectionViral infectionInfectionLung airwaysImpaired abilityChronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1
Parish IA, Marshall HD, Staron MM, Lang PA, Brüstle A, Chen JH, Cui W, Tsui YC, Perry C, Laidlaw BJ, Ohashi PS, Weaver CT, Kaech SM. Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1. Journal Of Clinical Investigation 2014, 124: 3455-3468. PMID: 25003188, PMCID: PMC4109559, DOI: 10.1172/jci66108.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChronic DiseaseCytokinesInflammation MediatorsInterleukin-10Lymphocytic ChoriomeningitisLymphocytic choriomeningitis virusMAP Kinase Signaling SystemMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicPositive Regulatory Domain I-Binding Factor 1Receptors, Antigen, T-CellTh1 CellsT-Lymphocyte SubsetsTranscription FactorsConceptsChronic viral infectionsIL-10 expressionT cell responsesIL-10 productionIL-10Th1 cellsViral infectionT cellsBlimp-1Viral-specific T cell responsesChronic lymphocytic choriomeningitis virus (LCMV) infectionAntiviral T cell responsesCell responsesImmunosuppressive cytokine IL-10Virus-specific T cellsLymphocytic choriomeningitis virus infectionChronic LCMV infectionImmunoregulatory IL-10Relevant cellular sourceCytokine IL-10Effector T cellsLCMV-infected micePersistent viral infectionT cell compartmentT cell functionImmune-Based Antitumor Effects of BRAF Inhibitors Rely on Signaling by CD40L and IFNγ
Ho PC, Meeth KM, Tsui YC, Srivastava B, Bosenberg MW, Kaech SM. Immune-Based Antitumor Effects of BRAF Inhibitors Rely on Signaling by CD40L and IFNγ. Cancer Research 2014, 74: 3205-3217. PMID: 24736544, PMCID: PMC4063281, DOI: 10.1158/0008-5472.can-13-3461.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigen-Presenting CellsAntineoplastic AgentsCD40 LigandCD4-Positive T-LymphocytesDrug Screening Assays, AntitumorIndolesInterferon-gammaMacrophagesMelanoma, ExperimentalMiceMice, TransgenicMutation, MissenseProto-Oncogene Proteins B-rafSignal TransductionSkin NeoplasmsSulfonamidesTumor MicroenvironmentConceptsTumor-infiltrating lymphocytesIFNγ expressionMyeloid cellsImmune stimulatory microenvironmentTh1 effector functionRegulatory T cellsAgonistic CD40 antibodyImmune-related changesTumor-bearing miceSuppress tumor growthIFNγ blockadeImmunologic changesAntitumor immunityAntitumor responseCD40 antibodyTumor regressionT cellsBRAF inhibitorsMurine modelEffector functionsImmunosuppressive featuresAntitumor effectsHost immunityMelanoma growthTumor growthTLR4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A Differentially Regulate Effector and Memory CD8+ T Cell Differentiation
Cui W, Joshi NS, Liu Y, Meng H, Kleinstein SH, Kaech SM. TLR4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A Differentially Regulate Effector and Memory CD8+ T Cell Differentiation. The Journal Of Immunology 2014, 192: 4221-4232. PMID: 24659688, PMCID: PMC4071140, DOI: 10.4049/jimmunol.1302569.Peer-Reviewed Original ResearchConceptsT cell differentiationT cellsEffector cellsTLR ligandsToll/IL-1R domain-containing adapterClonal expansionMore memory T cellsMemory T cellsT cell memoryEffector cell expansionTLR4 ligand LPSMonophosphoryl lipid ARole of adjuvantsTLR4 ligand lipopolysaccharideCell differentiationGene expression signaturesMemory CD8LPS-TLR4TLR4 ligandMonophosphoryl lipidLigand LPSLigand lipopolysaccharideAb productionSecondary infectionCell memoryTranscription Factor STAT3 and Type I Interferons Are Corepressive Insulators for Differentiation of Follicular Helper and T Helper 1 Cells
Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM, Craft J. Transcription Factor STAT3 and Type I Interferons Are Corepressive Insulators for Differentiation of Follicular Helper and T Helper 1 Cells. Immunity 2014, 40: 367-377. PMID: 24631156, PMCID: PMC3992517, DOI: 10.1016/j.immuni.2014.02.005.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, ViralAntibody SpecificityB-LymphocytesCD4 AntigensCD4-Positive T-LymphocytesCell DifferentiationGene Expression ProfilingGene Expression RegulationGerminal CenterImmunoglobulin Class SwitchingInterferon Type ILymphocytic ChoriomeningitisLymphocytic choriomeningitis virusMiceMice, KnockoutSignal TransductionSTAT1 Transcription FactorSTAT3 Transcription FactorT-Lymphocytes, Helper-InducerTranscriptomeConceptsTfh cellsType I interferonI interferonViral infectionFollicular helper T cellsT helper 1 cellsAntigen-specific antibody productionGC B cell phenotypeHigh affinity antibody-secreting cellsTfh cell differentiationHelper T cellsB cell memoryLymphocytic choriomeningitis virusB-cell phenotypeAntibody-secreting cellsGerminal center B cellsEffector phenotypeReceptor blockadeAcute infectionFollicular helperIFN-inducible genesT cellsTranscription factor STAT3B cellsAntibody production