Immuno-Genomic Landscape of Cutaneous Melanoma Identifies a Prognostic and Immunotherapeutically Relevant Gene Signature

Abstract BackgroundThe tumorigenesis of Skin cutaneous melanoma (SKCM) is still a mystery. Our study conducted a comprehensive analysis of the immune cell infiltration in the TME of SKCM. Based on the differential expression genes in the cluster grouped by the immune infiltration status, a set of hub genes related to the clinical prognosis of SKCM and tumor immune infiltration were explored.MethodsWe analyzed the immune cell infiltration in two independent cohorts, and then assessed the relationship between the internal pattern of immune cell infiltration and SKCM characteristics, including clinicopathological features, potential biological pathways and gene mutations. We further divided the three clusters of differential genes into two groups with different unique biological processes. The Signature gene-A gene set was mainly manifested as exon skipping (ES) in SKCM patients, while the Signature gene-B gene set has no obvious alternative splicing form. Subsequently, we not only analyzed the genetic variation of the two signatures, but also constructed a ceRNA regulatory network..LASSO Cox regression was utilized to find the immune infiltration signature and the risk score of SKCM. ResultWe finally obtained 13 Hub genes, and calculated the risk score based on the coefficient of each gene to further explore the impact of the high and low-risk score on the biologically related functions and prognosis of SKCM patients.The correlation between the risk score and the clinicopathological characteristics of SKCM patients indicated that the low risk score was associated with TMECluster-A classification (P <0.001) and metastatic SKCM (P <0.001). We finally obtained 13 Hub genes which showed different prognostic effects in pan-cancers. The IHC staining results showed that Ube2L6, SRPX2, IFIT2 were higher expression while CLEC4E, END3, KIR2DL4 were lower expression in 25 melanoma specimens.ConclusionWe performed a comprehensive assessment of SKCM's immune environment and constructed a set of unprecedented immune signatures related to the immune landscape (EDN3、CLEC4E、SRPX2、KIR2DL4、UBE2L6、IFIT2), which are correlated with the different prognosis and drug response of SKCM. The immune gene signature we constructed can be used as a robust prognostic biomarker of SKCM and a predictor of immunotherapy effect.