β-Catenin–mediated immune evasion pathway frequently operates in primary cutaneous melanomas
Jérémie Nsengimana, Jon Laye, Anastasia Filia, Sally O’Shea, Sathya Muralidhar, Joanna Poźniak, Alastair Droop, May Chan, Christy Walker, Louise Parkinson, Joanne Gascoyne, Tracey Mell, Minttu Polso, Rosalyn Jewell, Juliette Randerson-Moor, Graham P. Cook, D. Timothy Bishop, Julia Newton-Bishop
Jérémie Nsengimana, Jon Laye, Anastasia Filia, Sally O’Shea, Sathya Muralidhar, Joanna Poźniak, Alastair Droop, May Chan, Christy Walker, Louise Parkinson, Joanne Gascoyne, Tracey Mell, Minttu Polso, Rosalyn Jewell, Juliette Randerson-Moor, Graham P. Cook, D. Timothy Bishop, Julia Newton-Bishop
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Concise Communication Immunology Oncology

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

Abstract

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.

Authors

Jérémie Nsengimana, Jon Laye, Anastasia Filia, Sally O’Shea, Sathya Muralidhar, Joanna Poźniak, Alastair Droop, May Chan, Christy Walker, Louise Parkinson, Joanne Gascoyne, Tracey Mell, Minttu Polso, Rosalyn Jewell, Juliette Randerson-Moor, Graham P. Cook, D. Timothy Bishop, Julia Newton-Bishop

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Figure 2

Association of immune scores with evasion mechanisms.

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Association of immune scores with evasion mechanisms. (A) Distribution o...
(A) Distribution of selected immune cell scores in 6 CICs (pooled training and test LMC, n = 703). (B) Correlation and ratio between adaptive and innate immune scores (LMC). Owing to the high correlation between adaptive and innate scores, their ratios show a little variation between CICs. In A and B, R2 is the proportion of variance explained by the 6 CICs computed in ANOVA. Dot plots are shown alongside box plots showing the median and the interquartile range. (C) Correlations in LMC and TCGA (n = 472) between (a) 5 cell scores; (b) checkpoint and other regulatory genes; (c) β-catenin signaling genes; and (d) keratin and filaggrin expression. Based on the immune genes and keratin expression, the 6 CICs were described as low immune/β-catenin low (CIC1), high immune (CIC2), intermediate immune/keratin poor (CIC3), low immune/β-catenin high (CIC4), intermediate immune/keratin rich (CIC5), and low immune/keratin rich (CIC6).