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β-Catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas

Lookup NU author(s): Dr Jérémie Nsengimana

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2018 Academic Press. All rights reserved.Immunotherapy prolongs survival in only a subset of melanoma patients, highlighting the need to better understand the driver tumor microenvironment. We conducted bioinformatic analyses of 703 transcriptomes to probe the immune landscape of primary cutaneous melanomas in a population-ascertained cohort. We identified and validated 6 immunologically distinct subgroups, with the largest having the lowest immune scores and the poorest survival. This poor-prognosis subgroup exhibited expression profiles consistent with β-catenin-mediated failure to recruit CD141+ DCs. A second subgroup displayed an equally bad prognosis when histopathological factors were adjusted for, while 4 others maintained comparable survival profiles. The 6 subgroups were replicated in The Cancer Genome Atlas (TCGA) melanomas, where β-catenin signaling was also associated with low immune scores predominantly related to hypomethylation. The survival benefit of high immune scores was strongest in patients with double-WT tumors for BRAF and NRAS, less strong in BRAF-V600 mutants, and absent in NRAS (codons 12, 13, 61) mutants. In summary, we report evidence for a β-catenin-mediated immune evasion in 42% of melanoma primaries overall and in 73% of those with the worst outcome. We further report evidence for an interaction between oncogenic mutations and host response to melanoma, suggesting that patient stratification will improve immunotherapeutic outcomes.

Publication metadata

Author(s): Nsengimana J, Laye J, Filia A, O'Shea S, Muralidhar S, Pozniak J, Droop A, Chan M, Walker C, Parkinson L, Gascoyne J, Mell T, Polso M, Jewell R, Randerson-Moor J, Cook GP, Timothy Bishop D, Newton-Bishop J

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2018

Volume: 128

Issue: 5

Pages: 2048-2063

Online publication date: 16/04/2018

Acceptance date: 27/02/2018

Date deposited: 25/06/2020

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation

URL: https://doi.org/10.1172/JCI95351

DOI: 10.1172/JCI95351

PubMed id: 29664013

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