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; Annette Paschen

doi:10.1038/ncomms15440

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

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

Authors

Antje Sucker^{1

2}, Fang Zhao^{1

2}, Natalia Pieper^{1

2}, Christina Heeke^{1

2}, Raffaela Maltaner^{1

2}, Nadine Stadtler^{1

2}, Birgit Real^{1

2}, Nicola Bielefeld^{1

2}, Sebastian Howe³, Benjamin Weide⁴, Ralf Gutzmer⁵, Jochen Utikal⁶, Carmen Loquai⁷, Helen Gogas⁸, Ludger Klein-Hitpass⁹, Michael Zeschnigk¹⁰, Astrid M Westendorf¹¹, Mirko Trilling³, Susanne Horn^{1

2}, Bastian Schilling^{1

2

12}, Dirk Schadendorf^{1

2}, Klaus G Griewank^{1

2}, Annette Paschen^{1

2}

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigen Presentation / genetics
Antigens, Neoplasm / immunology
Antineoplastic Agents, Immunological / pharmacology
Antineoplastic Agents, Immunological / therapeutic use
Biopsy
Cell Line, Tumor
DNA Mutational Analysis
Datasets as Topic
Drug Resistance, Neoplasm / genetics*
Drug Resistance, Neoplasm / immunology
Histocompatibility Antigens Class I / immunology
Humans
Immunotherapy / methods
Interferon-gamma / immunology*
Interferon-gamma / metabolism
Janus Kinase 1 / genetics
Janus Kinase 1 / metabolism
Janus Kinase 2 / genetics
Janus Kinase 2 / metabolism
Melanoma / drug therapy
Melanoma / genetics*
Melanoma / immunology
Melanoma / pathology
Mutation
Mutation Rate
Patient-Specific Modeling
Precision Medicine / methods
Signal Transduction / genetics
Signal Transduction / immunology
Skin / pathology
Skin Neoplasms / drug therapy
Skin Neoplasms / genetics*
Skin Neoplasms / immunology
Skin Neoplasms / pathology
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism
Treatment Outcome
Tumor Escape / genetics*
Whole Genome Sequencing

Substances

Antigens, Neoplasm
Antineoplastic Agents, Immunological
Histocompatibility Antigens Class I
Interferon-gamma
JAK1 protein, human
JAK2 protein, human
Janus Kinase 1
Janus Kinase 2