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

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 and Annette Paschen ()
Additional contact information
Antje Sucker: University Hospital Essen, University Duisburg-Essen
Fang Zhao: University Hospital Essen, University Duisburg-Essen
Natalia Pieper: University Hospital Essen, University Duisburg-Essen
Christina Heeke: University Hospital Essen, University Duisburg-Essen
Raffaela Maltaner: University Hospital Essen, University Duisburg-Essen
Nadine Stadtler: University Hospital Essen, University Duisburg-Essen
Birgit Real: University Hospital Essen, University Duisburg-Essen
Nicola Bielefeld: University Hospital Essen, University Duisburg-Essen
Sebastian Howe: Institute of Virology, University Hospital Essen, University Duisburg-Essen
Benjamin Weide: University Medical Center Tübingen
Ralf Gutzmer: Skin Cancer Center Hannover, Hannover Medical School
Jochen Utikal: German Cancer Research Center (DKFZ), Skin Cancer Unit, Heidelberg and University Medical Center Mannheim, Venereology and Allergology, Ruprecht-Karl University of Heidelberg
Carmen Loquai: Skin Cancer Center, University of Mainz Medical Center
Helen Gogas: First Department of Medicine,National and Kapodistrian University of Athens
Ludger Klein-Hitpass: Institute of Cell Biology, University Hospital Essen, University of Duisburg-Essen
Michael Zeschnigk: Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK)
Astrid M. Westendorf: Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen
Mirko Trilling: Institute of Virology, University Hospital Essen, University Duisburg-Essen
Susanne Horn: University Hospital Essen, University Duisburg-Essen
Bastian Schilling: University Hospital Essen, University Duisburg-Essen
Dirk Schadendorf: University Hospital Essen, University Duisburg-Essen
Klaus G. Griewank: University Hospital Essen, University Duisburg-Essen
Annette Paschen: University Hospital Essen, University Duisburg-Essen

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15440

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