Identifying biomarkers associated with immunotherapy response in melanoma by multi-omics analysis

Despite immune checkpoint inhibitors (ICIs) have shown the greatest success in melanoma treatment, only a subset of melanoma patients responds well to ICIs. Thus, identifying predictive biomarkers for immunotherapy response is crucial. In this study, we took complementary advantages of immunotherapy data and The Cancer Genome Atlas (TCGA) multi-omics data to explore the predictive biomarkers for the response to immunotherapy in melanoma. We first predicted responsive and non-responsive melanomas in the TCGA skin cutaneous melanoma (SKCM) cohort based on both somatic mutation and transcriptome datasets which involved immunotherapy data for melanoma. This method identified 170 responsive and 56 non-responsive melanomas in TCGA-SKCM. Based on the TCGA-SKCM data, we performed a comprehensive comparison of multi-omics molecular features between responsive and non-responsive melanomas. We identified the molecular features significantly associated with immunotherapy response in melanoma at the genome, transcriptome, epigenome, and proteome levels, respectively. Our analysis confirmed certain immunotherapy response-associated biomarkers, such as tumor mutation burden (TMB), copy number alteration (CNA), intratumor heterogeneity (ITH), PD-L1 expression, and tumor immunity. Moreover, we identified some novel molecular features associated with immunotherapy response: (1) the activation of mast cells and dendritic cells correlating negatively with immunotherapy response; (2) the enrichment of many oncogenic pathways correlating positively with immunotherapy response, such as JAK-STAT, RAS, MAPK, HIF-1, PI3K-Akt, and VEGF pathways; and (3) a number of microRNAs and proteins whose expression correlates with immunotherapy response. In addition, the mTOR signaling pathway has a negative association with immunotherapy response. The novel biomarkers have potential predictive values in immunotherapy response and warrant further investigation.