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.

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma

“…The mechanisms underlying interpatient heterogeneity of immune response in GBM are unclear . β‐catenin‐mediated immune evasion pathways operate in CIC4, the group with the poorest prognosis in melanoma , whereas in this study we found no evidence of CTNNB1 differential expression between CIC2 and CIC4, nor was their mutational burden significantly different. However, GBM arises through various combinations of oncogene and tumour suppressor mutations, and several of these genes regulate tumour immune responses .…”

“…Indeed, melanoma shows interpatient heterogeneity of immune responses, and regarding melanoma as 'hot' fails to account for this variability. In melanoma, immune heterogeneity impacts upon survival [14] and the success of immunotherapy, with high expression of PD-1, CD8 + T cell infiltration and higher mutational burden associating with response to therapy [9]. We found no evidence for differential survival in GBM according to our CIC classifications, suggesting that the extensive immunosuppressive network removes any impact of immune control on GBM progression.…”

“…We found that CIC2 was significantly enriched for tumours of the mesenchymal subtype [34] (Supporting information, Table S2) that has been previously shown to have prolonged survival [21]. However, unlike melanoma [14], immune infiltration (reflected in the CIC clusters) was not associated with significant differences in survival in GBM (Supporting information, Fig. S5).…”

“…The number of patients in each CIC is indicated in brackets. The cell signatures used to derive the CIC [14] are shown. (b) Mutational load in GBM CIC2 (red) and CIC4 (green) expressed as mutations per megabase.…”

OMIC signatures to understand cancer immunosurveillance and immunoediting: Melanoma and immune cells interplay in immunotherapy

“…Nsengimana et al somehow reached a similar conclusion to Spranger et al. This group categorized 703 primary cutaneous melanomas based on their transcriptional profiles . Six clusters were identified, and among those with the worst survival were the ones with a β‐catenin‐high signal.…”