Melanoma-intrinsic β-catenin Signalling Prevents Anti-Tumour Immunity

Nature. 2015 Jul 9;523(7559):231-5. doi: 10.1038/nature14404. Epub 2015 May 11.

Abstract

Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches. These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferentially achieved in patients with a pre-existing T-cell response against their tumour, as evidenced by a baseline CD8(+) T-cell infiltration within the tumour microenvironment. Understanding the molecular mechanisms that underlie the presence or absence of a spontaneous anti-tumour T-cell response in subsets of cases, therefore, should enable the development of therapeutic solutions for patients lacking a T-cell infiltrate. Here we identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models we identified the mechanism by which tumour-intrinsic active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. Specific oncogenic signals, therefore, can mediate cancer immune evasion and resistance to immunotherapies, pointing to new candidate targets for immune potentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunotherapy
  • Melanoma / immunology*
  • Melanoma / physiopathology*
  • Mice
  • Signal Transduction*
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment / immunology*
  • Wnt Proteins / immunology
  • beta Catenin / immunology*

Substances

  • Wnt Proteins
  • beta Catenin

Associated data

  • GEO/GSE63543