Abstract
Immunotherapies have dramatically improved survival outcome for patients with melanoma. MUC16 encodes cancer antigen 125 (CA125), which is frequently mutated in melanoma. In this study, we correlated the MUC16 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 MUC16 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 MUC16 mutations. Immune-suppressive M2 macrophages were enriched in patients with wild-type MUC16. Immune checkpoints expression (e.g., PD-L1, PD-1 and CTLA-4) was also elevated in patients with MUC16 mutations. Immune response relevant circuits were among the top enriched pathways in samples with MUC16 mutations. Patients with MUC16 mutations exhibited a significantly better prognosis. For patients who received immunotherapy, the presence of MUC16 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.
Highlights
Melanoma is characterized by rapid progression and poor survival [1]
We found that patients with mutated MUC16 had a significantly higher tumor mutation load (TML) than those without it (Figure 1A)
Previous clinical trials have revealed that patients with high TML could benefit more from immune checkpoint inhibitor (ICI) agents in melanoma and non-small cell lung cancer (NSCLC) [19, 20]
Summary
Melanoma is characterized by rapid progression and poor survival [1]. Early-stage localized melanoma patients could be effectively treated through surgical resection, but survival outcome for patients with distant metastases is always less favorable [2]. Owing to the emergence of immunotherapy, especially immune checkpoint inhibitor (ICI) therapy, prognosis for melanoma patients has dramatically improved [4,5,6]. The current broadly used biomarker of immune treatment response is tumor mutation load (TML). Other multiple microenvironment-based factors, such as immune checkpoints expression, proportion of tumor infiltration lymphocytes (TIL), and interferon gamma (IFNγ) signature, play vital roles in response to www.aging-us.com immunotherapy. Patients who harbor fewer markers may benefit less from such treatment. This raises the question whether there exist other factors that simultaneously affect more than one of the above listed biomarkers, which could provide better predictive value for immunotherapy
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