Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions
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 patie...
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| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
31 May 2017
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| In: |
Nature Communications
Year: 2017, Jahrgang: 8, Pages: 15440 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms15440 |
| Online-Zugang: | Verlag, LF, Volltext: http://dx.doi.org/10.1038/ncomms15440 Verlag, LF, Volltext: https://www.nature.com/articles/ncomms15440 
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| Verfasserangaben: | Antje Sucker, Fang Zhao, Natalia Pieper, Christina Heeke, Raffaela Maltaner, Nadine Stadtler, Birgit Real, Nicola Bielefeld, Sebastian Howe, Benjamin Weide, Ralf Gutzmer, Jochen Utikal, Carmen Loquai, Helen Gogas, Ludger Klein-Hitpass, Michael Zeschnigk, Astrid M. Westendorf, Mirko Trilling, Susanne Horn, Bastian Schilling, Dirk Schadendorf, Klaus G. Griewank & Annette Paschen |
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| 520 | |a 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. | ||
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