Abstract
Ulceration and immune status are independent prognostic factors for survival in melanoma patients. Herein univariate Cox regression analysis revealed 53 ulcer-immunity-related DEGs. We performed consensus clustering to divide The Cancer Genome Atlas (TCGA) cohort (n = 467) into three subtypes with different prognosis and biological functions, followed by validation in three merged Gene Expression Omnibus (GEO) cohorts (n = 399). Multiomics approach was used to assess differences among the subtypes. Cluster 3 showed relatively lesser amplification and expression of immune checkpoint genes. Moreover, Cluster 3 lacked immune-related pathways and immune cell infiltration, and had higher proportion of non-responders to immunotherapy. We also constructed a prognostic model based on ulceration and immune related genes in melanoma. EIF3B was a hub gene in the intersection between genes specific to Cluster 3 and those pivotal for melanoma growth (DepMap, https://depmap.org/portal/download/). High EIF3B expression in TCGA and GEO datasets was related to worst prognosis. In vitro models revealed that EIF3B knockdown inhibited melanoma cell migration and invasion, and decreased TGF-β1 level in supernatant compared with si-NC cells. EIF3B expression was negatively correlated with immune-related signaling pathways, immune cell gene signatures, and immune checkpoint gene expression. Moreover, its low expression could predict partial response to anti-PD-1 immunotherapy. To summarize, we established a prognostic model for melanoma and identified the role of EIF3B in melanoma progression and immunotherapy resistance development.