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.

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