title: Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.
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.
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Stefani
authors.initials: S
authors.lastname: Spranger
authors.affiliation: Center for Research Informatics, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Riyue
authors.initials: R
authors.lastname: Bao
authors.affiliation: 1] Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA [2] Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000276:immunology* / Q000503:physiopathology*; D051379:Mice; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*; D051153:Wnt Proteins / Q000276:immunology; D051176:beta Catenin / Q000276:immunology*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin