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.
Highlights
Melanoma is a highly aggressive skin malignant tumor that is prone to metastasis at an early stage and has the highest mortality rate among skin cancers [1]
We found that the proportion of patients with low immune infiltration is highest in cluster 3 (51.2%) and most of the samples in cluster3 were defined as ulceration (78.6%)
Considering that there exists strong evidence regarding the importance of ulceration and immune checkpoint inhibitors in the prognosis of melanoma, we identified a prognostic model based on ulceration and immune related genes, providing clues for prognosis prediction of melanoma
Summary
Melanoma is a highly aggressive skin malignant tumor that is prone to metastasis at an early stage and has the highest mortality rate among skin cancers [1]. The prognostic risk factors of malignant melanoma include fraction of tumor infiltrating lymphocytes [4, 5], and tumor stage including tumor thickness and ulceration [6]. Immunotherapy (e.g., anti-PD-1 therapy) has been found to significantly reduce the mortality of melanoma in recent years [7], numerous patients still develop resistance, and the mortality rate continues to remain high [8]. According to previous studies, immune cell infiltration in patients with melanoma is related to an improvement in the survival rate and response to immunotherapy [4, 11]. The low tumor infiltrating lymphocytes combined with presence of ulceration accelerates melanoma progression [4, 15]. It is necessary to comprehensively understand the molecular characteristics of patients showing a combination of ulceration and immune cell infiltration
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