Distinct Genomic Features Across Cytolytic Subgroups In Skin Melanoma

Abstract Background: Skin melanoma is a highly immunogenic cancer with extensive genetic and transcriptional diversity. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibition, a subgroup of them later relapse and develop acquired resistance. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T cells and NK cells to eliminate cancer cells, and is associated with improved patient survival. Here, we questioned whether CYT associates with different genomic profiles in skin melanoma. Methods: We explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen.garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Results: Metastatic skin melanomas had significantly higher CYT compared to primary tumors. We also assessed enrichment for immune-related gene sets within CYT-high tumors; whereas, CYT-low tumors were enriched for non-immune related genes sets. In addition, distinct mutational and neoantigenic loads, primarily composed of C>T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where non-telomeric chromosomal regions harboring chromothripsis, contained a higher number of cancer genes. CYT-high patients had markedly higher immunophenoscore and should consequently, display an expected clinical benefit compared to CYT-low patients who either received or not, checkpoint inhibition. Conclusions: Overall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma.