TY - JOUR
TI - Acquired IFNγ 3 resistance impairs anti-Tumor immunity and gives rise to T-cell-resistant melanoma lesions
AU - Sucker, A.
AU - Zhao, F.
AU - Pieper, N.
AU - Heeke, C.
AU - Maltaner, R.
AU - Stadtler, N.
AU - Real, B.
AU - Bielefeld, N.
AU - Howe, S.
AU - Weide, B.
AU - Gutzmer, R.
AU - Utikal, J.
AU - Loquai, C.
AU - Gogas, H.
AU - Klein-Hitpass, L.
AU - Zeschnigk, M.
AU - Westendorf, A.M.
AU - Trilling, M.
AU - Horn, S.
AU - Schilling, B.
AU - Schadendorf, D.
AU - Griewank, K.G.
AU - Paschen, A.
JO - Nature Communications
PY - 2017
VL - 8
TODO - null
SP - null
PB - Nature Publishing Group
SN - 2041-1723
TODO - 10.1038/ncomms15440
TODO - 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
TODO - 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).
ER -