Thursday, May 9, 2024
5/9/2024
Title: Glioblastoma-secreted GABA contributes to the immunosuppressive environment Abstract: Glioblastoma (GBM) is one of the most common and lethal human brain tumors and there are no effective treatments. We have shown that immune cells have GABA-receptors (GABA-Rs) and that their activation limits inflammatory immune responses. Indeed, three recent studies of several different types of peripheral solid tumors have demonstrated that tumor cells, or B cells within tumors, can secrete GABA which dramatically shifts the phenotype of human and murine tumor-infiltrating macrophages and dendritic cells towards anti-inflammatory phenotypes and inhibits the activity of infiltrating CD8+ effector T cells, consistent with our findings of GABA’s action in autoimmune diseases. GABA-R antagonists, or inactivation of the GABA- synthesizing enzyme glutamic acid decarboxylase (GAD67), significantly decreases tumor burden in these models. Thus, GABA is an important intra-tumor immunosuppressive factor in these peripheral tumors. There are multiple lines of evidence indicating that glioblastoma cells secrete high levels of GABA. Our central hypothesis is that GBM-secreted GABA contributes to the immunosuppressive tumor environment. Our proposed studies with GAD67-deficient GBM cell lines will determine 1) whether GBM-secreted GABA modulates the frequency, phenotype, and localization of tumor infiltrating immune cells, 2) how GABA deficiency modulates GBM gene expression, and 3) whether rendering GBMs GABA-deficient confers a survival advantage. These investigations will collectively provide the first understanding of how GBM-secreted GABA transforms the tumor microenvironment and affects survival. If our central hypothesis is supported, future studies can examine whether making anti-tumor responses resistant to GABA inhibition could improve their effector functions. For example, we may be able to enhance the effectiveness of NK, DC, or T cell-based therapies by making them GABA-R deficient. Alternatively, new therapies may be designed to specifically target immune cell GABA-Rs or their signaling pathways.
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