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IFN\u03b3 secretion by CD8<jats:sup>+<\/jats:sup> T cells is critical for therapy efficacy having anti-proliferative and pro-apoptotic effects on tumour cells. Our study demonstrates a genetic evolution of IFN\u03b3 resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFN\u03b3 signalling cascade, most often <jats:italic>JAK1<\/jats:italic> or <jats:italic>JAK2,<\/jats:italic> protect melanoma cells from anti-tumour IFN\u03b3 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 IFN\u03b3. Allelic <jats:italic>JAK1\/2<\/jats:italic> losses predisposing to IFN\u03b3 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 IFN\u03b3 activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFN\u03b3 resistance should be considered in therapeutic decision-making.<\/jats:p>","DOI":"10.1038\/ncomms15440","type":"journal-article","created":{"date-parts":[[2017,5,31]],"date-time":"2017-05-31T12:10:18Z","timestamp":1496232618000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":252,"title":["Acquired IFN\u03b3 resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions"],"prefix":"10.1038","volume":"8","author":[{"given":"Antje","family":"Sucker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Pieper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Heeke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaela","family":"Maltaner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Stadtler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Real","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Bielefeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Howe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Weide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Gutzmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Utikal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Loquai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Gogas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludger","family":"Klein-Hitpass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zeschnigk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid M.","family":"Westendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Trilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Horn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastian","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Schadendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus G.","family":"Griewank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Paschen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,5,31]]},"reference":[{"key":"BFncomms15440_CR1","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.coi.2011.12.009","volume":"24","author":"SL Topalian","year":"2012","unstructured":"Topalian, S. 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J.U.: advisory boards and on speaker\u0155s bureaus of Amgen, BMS, GSK, MSD, Novartis, and Roche. R.G.: research support from Novartis, Pfizer, Johnson&Johnson; honoraia for lectures from Roche Pharma, Bristol-MyersSquibb, GlaxoSmithKline, Novartis, Merck Serono, MSD, Almirall-Hermal, Amgen, Galderma, Janssen, Boehringer Ingelheim; paid advisory role for Roche Pharma, Bristol-MyersSquibb, GlaxoSmithKline, Novartis, MSD, Almirall-Hermal, LEO, Amgen, Pfizer. C.L.: Advisory\/Consultant or speakers fee from BMS, Roche, Amgen, Novartis, Pierre Fabre, Biontech, MSD. B.S.: advisory board or honoraria from Novartis, Roche, Bristol-Myers Squibb and MSD Sharp & Dohme, research funding from Bristol-Myers Squibb and MSD Sharp & Dohme, travel support from Novartis, Roche, Bristol-Myers Squibb and AMGEN. D.S.: advisory board or honoraria from Roche, Genentech, Novartis, Amgen, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck Sharp & Dohme. All other authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15440"}}