Tumor subclones harbouring inactivating mutations in the IFNγ signaling pathway can be detected in pretreatment biopsies of some melanoma patients or can emerge during immunotherapy treatment, and in some cases IFNγ-resistant melanoma progresses further through silencing of HLA class I antigen presentation, leading to complete CD8+ T-cell resistance.
Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFNgamma 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 IFNgamma resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFNgamma signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-tumour IFNgamma 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 IFNgamma. Allelic JAK1/2 losses predisposing to IFNgamma 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 IFNgamma activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFNgamma resistance should be considered in therapeutic decision-making.
Author Info: (1) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Ess
Author Info: (1) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (2) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (3) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (4) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (5) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (6) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (7) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (8) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (9) Institute of Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. (10) Division of Dermatooncology, Department of Dermatology, University Medical Center Tubingen, 72076 Tubingen, Germany. (11) Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, 30625 Hannover, Germany. (12) 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. (13) Skin Cancer Center, Department of Dermatology, University of Mainz Medical Center, 55131 Mainz, Germany. (14) First Department of Medicine,National and Kapodistrian University of Athens, 11527 Athens, Greece. (15) Institute of Cell Biology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany. (16) Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, West German Cancer Center and the German Cancer Consortium (DKTK), 45122 Essen, Germany. (17) Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany. (18) Institute of Virology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. (19) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (20) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. Department of Dermatology, Venereology and Allergology, University Hospital Wurzburg, 97080 Wurzburg, Germany. (21) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (22) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany. (23) Department of Dermatology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany. German Cancer Consortium (DKTK), partner site Essen/Dusseldorf, 45122 Essen, Germany.
