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

S Spranger, R Bao, TF Gajewski - Nature, 2015 - nature.com
Nature, 2015nature.com
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,,). 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 …
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 , , ). 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.
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