Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches1,2. 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 microenvironment6,7. 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 models8,9 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.
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Gene Expression Omnibus
Gene array data have been deposited in the Gene Expression Omnibus under accession number GSE63543.
The authors would like to thank A. Sailer and J. Turner for their assistance on mouse tissue immunofluorescent staining, M. Leung and Y. Zha for technical support, and the Special Services Animal Resources Center for assistance with mouse husbandry. We also acknowledge the Fitch Monoclonal Antibody Facility, the Human Tissue Research Core and the Integrated Microscopy core of The University of Chicago Comprehensive Cancer Center. We would like to thank A. O. Emmanuel and F. Gounari for assistance with the ChIP assay as well as for conditional β-catenin knock-in mice; C. Slingluff, D. Deacon, J. Schaefer, G. Erdag and the University of Virginia Biorepository and Tissue Research Facility for melanoma biopsy specimens, and P. Savage for critical comments. Funding for this study was provided by a Team Science Award from the Melanoma Research Alliance and a Translational Research Grant from the Cancer Research Institute. S.S. was supported by the German Research Foundation and is currently a fellow of the Cancer Research Institute.
Extended data figures
This file contains Supplementary Tables 1-5 comprising:1 (a) Expression of T cell genes in segregated groups (b) Gene clusters after supervised hierarchical clustering (c) List of differentially expressed genes; 2 - Pearson correlation of β-catenin target genes and CD8a transcripts; 3 - Mutation analysis summary with (a) T cell signature low patients and (b) T cell signature high patients (c) Table summarizing potential pathway activators in patients with an active β-catenin signature; 4 - Mouse gene array data of differentially expressed genes (a) and a summary table focusing on chemokine expression (b); 5 - Detailed primer and antibody information (a) Genotyping primers (b) antibodies (c) qPCR primer/ probes (d) ChIP assay primer and (e) siRNA oligos.
About this article
Frontiers in Immunology (2019)