IMMU-09. GABA–L-Arginine signaling in gMDSCs drives immunosuppression in female glioblastoma

Abstract Myeloid-derived suppressor cells (MDSCs) are key mediators of immunosuppression within the glioblastoma (GBM) tumor microenvironment (TME). We previously demonstrated that expansion of granulocytic MDSCs (gMDSCs) promotes GBM progression specifically in females. However, the host factors driving this sex-dependent MDSC behavior remain largely unexplored. Here, we identify γ-aminobutyric acid (GABA) signaling as a novel modulator of gMDSC function. We found that gMDSCs express GABA receptor B (GABBR), and GABBR activation selectively enhanced intracellular L-arginine levels, nitric oxide synthase 2 (NOS2) expression, and T cell suppressive capacity in female, but not male, gMDSCs. In preclinical GBM models, treatment with the GABBR agonist baclofen accelerated tumor progression in females through NOS2-, gMDSC- and immune-dependent mechanisms, accompanied by increased T cell suppression in the TME. In contrast, GABBR blockade using CGP35348 prolonged survival in female GBM models in a gMDSC-dependent manner and reduced NOS2 expression in tumor-infiltrating gMDSCs. Mechanistically, the immunosuppressive effect of GABBR signaling was contingent on L-arginine availability. Deletion of the cationic amino acid transporter 2 (Cat2) abrogated GABBR-mediated NOS2 induction, and dietary L-arginine restriction extended survival in GBM models. Importantly, analysis of patient samples revealed elevated levels of GABA, L-arginine, and GABBR expression in tumor-infiltrating myeloid cells from females compared to males. These findings reveal a sex-specific GABAergic axis that promotes immune suppression in GBM through modulation of gMDSC metabolism and function. Targeting the GABBR-L-arginine-NOS2 pathway may offer a novel immunotherapeutic approach for female GBM patients.