@article{3026238,
    title = "Acquired IFNγ 3 resistance impairs anti-Tumor immunity and gives rise to T-cell-resistant melanoma lesions",
    author = "Sucker, A. and Zhao, F. and Pieper, N. and Heeke, C. and Maltaner, R. and Stadtler, N. and Real, B. and Bielefeld, N. and Howe, S. and Weide, B. and Gutzmer, R. and Utikal, J. and Loquai, C. and Gogas, H. and Klein-Hitpass, L. and Zeschnigk, M. and Westendorf, A.M. and Trilling, M. and Horn, S. and Schilling, B. and Schadendorf, D. and Griewank, K.G. and Paschen, A.",
    journal = "Nature Communications",
    year = "2017",
    volume = "8",
    publisher = "Nature Publishing Group",
    issn = "2041-1723",
    doi = "10.1038/ncomms15440",
    keywords = "gamma interferon;  Janus kinase 1;  Janus kinase 2;  gamma interferon;  HLA antigen class 1;  immunological antineoplastic agent;  JAK1 protein, human;  JAK2 protein, human;  Janus kinase 1;  Janus kinase 2;  tumor antigen, allele;  antigen;  cells and cell components;  decision making;  gene expression;  genetic analysis;  immunity;  lesion;  mutation;  secretion;  tumor, antigen presentation;  antineoplastic activity;  Article;  cancer immunotherapy;  chromosome;  gene;  gene mutation;  genetics;  human;  human cell;  human tissue;  melanoma;  melanoma cell;  T lymphocyte;  tumor biopsy;  tumor immunity;  biological model;  biopsy;  dna mutational analysis;  drug resistance;  immunology;  immunotherapy;  information processing;  melanoma;  metabolism;  mutation;  mutation rate;  pathology;  personalized medicine;  procedures;  secretion (process);  signal transduction;  skin;  skin tumor;  T lymphocyte;  treatment outcome;  tumor cell line;  tumor escape;  whole genome sequencing, Antigen Presentation;  Antigens, Neoplasm;  Antineoplastic Agents, Immunological;  Biopsy;  Cell Line, Tumor;  Datasets as Topic;  DNA Mutational Analysis;  Drug Resistance, Neoplasm;  Histocompatibility Antigens Class I;  Humans;  Immunotherapy;  Interferon-gamma;  Janus Kinase 1;  Janus Kinase 2;  Melanoma;  Mutation;  Mutation Rate;  Patient-Specific Modeling;  Precision Medicine;  Signal Transduction;  Skin;  Skin Neoplasms;  T-Lymphocytes;  Treatment Outcome;  Tumor Escape;  Whole Genome Sequencing",
    abstract = "Melanoma treatment has been revolutionized by antibody-based immunotherapies. IFN 3 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 IFN 3 resistance in different melanoma patient models. Chromosomal alterations and subsequent inactivating mutations in genes of the IFN 3 signalling cascade, most often JAK1 or JAK2, protect melanoma cells from anti-Tumour IFN 3 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 IFN 3. Allelic JAK1/2 losses predisposing to IFN 3 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 IFN 3 activity and results in T-cell-resistant HLA class I-negative lesions. Screening for mechanisms of IFN 3 resistance should be considered in therapeutic decision-making. © 2017 The Author(s)."
}