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Nat Commun. 2017 May 31;8:15440. doi: 10.1038/ncomms15440.

Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions.

Author information

1
Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
2
German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, 45122 Essen, Germany.
3
Institute of Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
4
Division of Dermatooncology, Department of Dermatology, University Medical Center Tübingen, 72076 Tübingen, Germany.
5
Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, 30625 Hannover, Germany.
6
German Cancer Research Center (DKFZ), Skin Cancer Unit, Heidelberg and University Medical Center Mannheim, Department of Dermatology, Venereology and Allergology, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany.
7
Skin Cancer Center, Department of Dermatology, University of Mainz Medical Center, 55131 Mainz, Germany.
8
First Department of Medicine,National and Kapodistrian University of Athens, 11527 Athens, Greece.
9
Institute of Cell Biology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
10
Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), 45122 Essen, Germany.
11
Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
12
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, 97080 Würzburg, Germany.

Abstract

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.

PMID:
28561041
PMCID:
PMC5460020
DOI:
10.1038/ncomms15440
[Indexed for MEDLINE]
Free PMC Article

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