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β-Catenin–mediated immune evasion pathway frequently operates in primary cutaneous melanomas
Jérémie Nsengimana, … , D. Timothy Bishop, Julia Newton-Bishop
Jérémie Nsengimana, … , D. Timothy Bishop, Julia Newton-Bishop
Published April 16, 2018
Citation Information: J Clin Invest. 2018;128(5):2048-2063. https://doi.org/10.1172/JCI95351.
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Concise Communication Immunology Oncology

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

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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 1

Tumor classification.

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Tumor classification.
(A) Consensus immunome clusters (CICs) in the LMC ...
(A) Consensus immunome clusters (CICs) in the LMC training (n = 465) and test (n = 238) data sets ordered according to the dendrogram output from ConsensusClusterPlus (see Supplemental Figure 3). The details of gene clusters G1–G4 are given in Supplemental Figure 4. (B) Differential melanoma-specific survival for patients with tumors in the 6 CICs in the training, test, and pooled data sets unadjusted for histological factors. Cluster size: 11%, 21%, 13%, 25%, 15%, and 15% for CICs 1–6, respectively. Cause of death was unknown or was not melanoma for 27 patients, and they were excluded from survival analysis.
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