High mutation load, immune-activated microenvironment, favorable outcome, and better immunotherapeutic efficacy in melanoma patients harboring /CA125 mutations.

Immunotherapies have dramatically improved survival outcome for patients with melanoma. encodes cancer antigen 125 (CA125), which is frequently mutated in melanoma. In this study, we correlated the mutational status with the following: tumor mutation burden (TML), multiple immune-related signals in microenvironment, deregulated pathways, survival outcome, and immunotherapeutic efficacy. We found that patients with mutations had significantly higher TML than those without it. Enriched pro-inflammatory CD8 T cells and M1 macrophages, enhanced interferon gamma (IFNγ) and T cell-inflamed signatures, and increased cytolytic activity were associated with mutations. Immune-suppressive M2 macrophages were enriched in patients with wild-type . Immune checkpoints expression (e.g., , and ) was also elevated in patients with mutations. Immune response relevant circuits were among the top enriched pathways in samples with mutations. Patients with mutations exhibited a significantly better prognosis. For patients who received immunotherapy, the presence of mutations was associated with a better response rate and survival outcome in male patients but not in female or overall patients. These findings provide new implications for tailoring immunotherapeutic strategies for melanoma patients.