TMIC-72. INVESTIGATING THE ROLES OF PGE2 IN MODULATING THE GBM-GAM MICROENVIRONMENT

Abstract

Abstract Glioblastoma (GBM), the most aggressive and deadliest primary brain tumor, is characterized by being surrounded by up to approximately 40% macrophages, which promote tumor progression through interactions with tumor cells. The mechanisms underlying how GBM and its associated macrophages (GAM) communicate remain not fully understood. In this study, we investigated the essential roles of Prostaglandin E2 (PGE2), which affects multiple functions of immune cells, in modulating the GBM microenvironment, specifically the GAM. Massive PGE2 accumulated in the GBM-GAM co-culture microenvironment, and the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) involved in PGE2 synthesis was markedly elevated in GAM. GAM expressed two PGE2 receptors, namely EP2 and EP4, and their expressions positively correlated with PTGS2 expression. Ingenuity pathway analysis (IPA) of differentially expressed (DE) genes obtained from GBM- (conditioned medium) CM-treated THP-1 macrophages revealed significant enrichment in biological functions associated with migration and proliferation. THP-1 macrophage migration promoted by GBM-CM was interrupted by blocking EP4 receptors using an antagonist. GBM-CM promoted THP-1 macrophages proliferation and increased proliferative enhancers, such as PI3KCD, AKT3, ETS1, and BHLHE41, while decreasing proliferative repressors, including MAF, MAFB, and CDKN1A. Cytokine array analysis indicated that GBM-CM shaped GAM into an immunosuppressive phenotype and elevated IL-6 secretion to promote GBM growth. In conclusion, our current results suggest that PGE2 accumulates in the GBM microenvironment, sustaining the macrophage population through increased recruitment and elevated local proliferation and shaping macrophages into an immunosuppressive type. Blockage of the PGE2 autocrine regulation, thus interrupting the supportive roles of GAM in GBM progression, may provide a novel therapeutic strategy for treating patients with GBM.