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RESEARCH PRODUCT
Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
Annette PaschenFang ZhaoSusanne HornHelen GogasDirk SchadendorfBenjamin WeideAntje SuckerBastian SchillingBastian SchillingJochen UtikalCarmen LoquaiLudger Klein-hitpassNadine StadtlerRaffaela MaltanerMichael ZeschnigkNicola BielefeldAstrid M. WestendorfBirgit RealNatalia PieperChristina HeekeRalf GutzmerMirko TrillingKlaus G. GriewankSebastian Howesubject
Patient-Specific Modeling0301 basic medicineSkin NeoplasmsBiopsyT-LymphocytesDNA Mutational AnalysisDatasets as TopicGeneral Physics and AstronomyAntineoplastic Agents ImmunologicalMutation RatePrecision MedicineMelanomaSkinAntigen PresentationMultidisciplinarybiologyMelanomaQfood and beverages3. Good healthTreatment Outcomemedicine.anatomical_structureImmunotherapyAntibodySignal TransductionScienceT cellAntigen presentationHuman leukocyte antigenArticleGeneral Biochemistry Genetics and Molecular BiologyInterferon-gamma03 medical and health sciencesAntigenAntigens NeoplasmCell Line TumormedicineHumansWhole Genome SequencingHistocompatibility Antigens Class IJanus Kinase 1General ChemistryJanus Kinase 2medicine.disease030104 developmental biologyImmunoeditingDrug Resistance NeoplasmMutationImmunologybiology.proteinTumor EscapeCD8description
Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNγ secretion by CD8+ T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFNγ resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNγ signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNγ activity. JAK1/2 mutants further evolve into T-cell-resistant HLA class I-negative lesions with genes involved in antigen presentation silenced and no longer inducible by IFNγ. Allelic JAK1/2 losses predisposing to IFNγ resistance development are frequent in melanoma. Subclones harbouring inactivating mutations emerge under various immunotherapies but are also detectable in pre-treatment biopsies. Our data demonstrate that JAK1/2 deficiency protects melanoma from anti-tumour IFNγ activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNγ resistance should be considered in therapeutic decision-making.
year | journal | country | edition | language |
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2016-09-07 | Nature Communications |