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.
Highlights
Melanoma is an immunogenic tumor, and the presence of histopathologically detected tumor-infiltrating lymphocytes (TILs) is associated with increased patient survival and reduced risk of metastasis [1]
Whole transcriptomes were derived from 703 formalin-fixed paraffin wax–embedded (FFPE) primary cutaneous melanomas from the Leeds Melanoma Cohort (LMC), using the Illumina DASL HT12.4 array
APC2, SOX2, SOX11, and MYC were all inversely correlated with double-WT tumors, but less so in BRAF-mutated and not at all in immune scores in the The Cancer Genome Atlas (TCGA) data set, while their highest expres- NRAS-mutated tumors (Figure 4B); these differences were not sion was observed in low immune/β-catenin high CIC4 (Sup- matched by differences in cell scores (Figure 1A)
Summary
Melanoma is an immunogenic tumor, and the presence of histopathologically detected tumor-infiltrating lymphocytes (TILs) is associated with increased patient survival and reduced risk of metastasis [1]. We have used a modification of this technique to characterize the heterogeneous immune landscape in 703 primary cutaneous melanomas from a population-ascertained cohort (the Leeds Melanoma Cohort [LMC]) [10, 11] and examined whether the inferred immune subgroups reflect patient survival characteristics. We have coupled this with an analysis of candidate immune evasion pathways and correlations with driver oncogene mutations and tested our findings in a second data set from The Cancer Genome Atlas (TCGA), which includes primarily metastatic tumors (n = 369) with a subset of primaries (n = 103). Our results highlight substantial heterogeneity in the immune landscape across melanoma primaries and metastases and show evidence for immune inhibition by β-catenin signaling in a significant proportion of tumors
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