Περίληψη:
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).
Συγγραφείς:
Sucker, A.
Zhao, F.
Pieper, N.
Heeke, C.
Maltaner, R.
Stadtler, N.
Real, B.
Bielefeld, N.
Howe, S.
Weide, B.
Gutzmer, R.
Utikal, J.
Loquai, C.
Gogas, H.
Klein-Hitpass, L.
Zeschnigk, M.
Westendorf, A.M.
Trilling, M.
Horn, S.
Schilling, B.
Schadendorf, D.
Griewank, K.G.
Paschen, A.
Λέξεις-κλειδιά:
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
