Multiomics Analysis of Malignant Pleural Mesothelioma Reveals the Immunological Microenvironment Associated with MTAP Loss and Immunotherapy Outcomes

PURPOSE: Nivolumab plus ipilimumab is a standard first-line therapy for unresectable malignant pleural mesothelioma (MPM), yet biomarkers predicting immune checkpoint inhibitor (ICI) efficacy remain undefined. We aimed to identify genomic and tumor immune microenvironmental features associated with ICI response in MPM. EXPERIMENTAL DESIGN: We analyzed two independent MPM cohorts. The discovery cohort included patients at the National Cancer Center Hospital (2012-2022) with frozen tumor tissues available for whole-genome sequencing (WGS) and RNA sequencing. Genomic alterations, transcriptomic profiles, immune cell composition, and T-cell receptor repertoire were analyzed, and key findings were validated in a nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) cohort. RESULTS: The WGS cohort comprised 52 patients. Among ICI-treated patients, overall response rates were 30% in the WGS cohort and 29.4% in the C-CAT cohort. Genomic analyses identified frequent alterations in BAP1 and NF2, across both cohorts. ICI responders showed higher T-cell receptor diversity, increased CD8⁺ T-cell infiltration, and enrichment of M1 macrophages compared with non-responders. MTAP loss was associated with higher CD8⁺ T-cell infiltration and T-cell receptor diversity, and was linked to a higher ICI response rate in the C-CAT cohort. In contrast, BAP1 and NF2 alterations showed no consistent association with immune features or ICI efficacy. CONCLUSIONS: An immune-active tumor microenvironment characterized by high T-cell receptor diversity, CD8⁺ T-cell infiltration, and M1 macrophage enrichment was associated with favorable ICI responses in MPM. MTAP loss was linked to immune-related features and a higher ICI response, supporting further investigation of MTAP loss as a candidate biomarker.