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

Spranger S, Bao R, Gajewski TF

Editorial Comment by Dr. James Larkin
The systemic treatment of advanced melanoma and a number of other tumour types is changing rapidly as a consequence of the development of immune checkpoint inhibitors such as antibodies to CTLA4, PD1 and PD-L1. Nevertheless even in melanoma, the malignancy most sensitive to these drugs, only a minority of patients benefit from single agent therapy and it may be that this minority is characterised by is a pre-existing T-cell response against the tumour, as evidenced by a baseline CD8+ T-cell tumour infiltration. Thus understanding the basis of a spontaneous T-cell response to the tumour may allow the development of therapies for tumours lacking a T-cell infiltrate. Spranger and colleagues in this work identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltrate. Specifically, analysis of human metastatic melanoma samples showed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. In mouse models a mechanism was identified by which tumour-intrinsic active β-catenin signalling resulted in T-cell exclusion and resistance to anti-CTLA-4/anti-PD-L1 therapy. The authors conclude that specific oncogenic signals can mediate resistance to immunotherapies, opening up the possibility of developing therapeutic strategies to counteract such resistance.

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.