Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity

Only a subset of patients with melanoma responds to new immunotherapeutic therapies; here, β-catenin signalling is identified as an important pathway that confers resistance to this type of approach, with implications for future treatment strategies. WNT/β-catenin target in drug-resistant melanoma Only a subset of patients with melanoma responds to the new wave of immune-based therapies. Here Stefani Spranger et al . identify active WNT/β-catenin signalling as a common feature in melanomas showing resistance to immunotherapies that act via checkpoint blockage by anti-PD-L1 or anti-CTLA-4, a phenomenon associated with the exclusion of T cells from the tumour microenvironment. This work points to β-catenin as an example of specific oncogenic signal that could be targeted as part of an anti-tumour treatment strategy. Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches 1 , 2 . 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 , 4 , 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 6 , 7 . 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 8 , 9 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.