Background Skin melanoma is a highly immunogenic cancer. 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. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors (ICI), a subgroup of them will later relapse and develop acquired resistance. 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. We calculated the tumor immune contexture, somatic mutations, recurrent copy number aberrations, chromothripsis, cancer neoepitopes, immunophenoscore, mutational signatures, kataegis and strand asymmetry in each cytolytic subgroup.

Results CYT was higher in enriched in immune-related gene sets metastatic tumors. Distinct mutational and neoantigen loads, primarily composed of C>T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. More chromothripsis events were found across CYT-low tumors SBS7a/b, SBS5 and SBS1 were the most prevalent mutational signatures in both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a/b were mutually exclusive with SBS5 and SBS1 in both CYT subgroups. Mutational strand asymmetries related to the processes of DNA transcription and replication differed between CYT-high and CYT-low tumors. 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, ICI.

Conclusions Our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma patients, which could affect their relapse rate or resistance to ICI.