332P Integrated transcriptomic profiling reveals limited immune microenvironment remodeling in pleural mesothelioma

Background:The cyclic GMP-AMP synthase (cGAS)/STING pathway, a central DNAsensing mechanism, is known to activate anti-tumor immune response but may also promote tumor progression when chronically activated.Given the role of asbestosinduced chronic inflammation in pleural mesothelioma (PM), we investigated cGAS/ STING expression and its association with treatment outcomes. Methods:We analyzed tissue micro arrays (TMAs) from 190 PM patients using multiparameter immunofluorescence single-cell imaging.cGAS and STING expression were quantified in tumor cells, non-tumor cells and CD8+ T cells before and after platinum-based chemotherapy Associations with treatment response and survival were assessed. Results:We show that chemotherapy significantly increased cGAS expression in CD8+ T cells and especially in non-tumor cells (+24-29%, p < 0.0001) while STING levels remained unchanged.Patients with progressive disease showed higher cGAS upregulation after chemotherapy compared to those with partial response or stable disease (p = 0.0004).Survival analysis revealed that low baseline cGAS expression was associated with longer progression-free survival (p = 0.003), mostly due to cGAS expression in non-tumor cells (p = 0.0048) and CD8+ T cells (p = 0.042), but not in tumor cells.Using TCGA PM cohort, we confirmed that low cGAS mRNA expression correlated with improved overall survival (p = 0.043). Conclusions:Low baseline cGAS expression predicts favorable progression-free survival and treatment response in PM, suggesting a pro-tumorigenic role for cGAS in PM.These results identify cGAS as a potential predictive biomarker for chemotherapy response and highlight the importance of DNA-sensing pathways.