-aminobutyric acid drives glioblastoma in females in an immune-dependent manner

Abstract Interaction between tumor cells and neurons drives the progression of glioblastoma (GBM), which is characterized by enhanced immunosuppressive myeloid cell accumulation. Our previous results revealed that myeloid-derived suppressor cell subsets (MDSCs) play a critical role in tumorigenesis in a sex-specific manner, with monocytic MDSCs (mMDSCs) accumulating in male tumors and granulocytic MDSCs (gMDSCs) correlating with a worse outcome in females. However, host factors governing sex differences in MDSC subset activity remained unknown. Here, we report that gMDSCs express g-aminobutyric acid (GABA) receptor and female gMDSCs respond to GABA by upregulating the antiviral innate immune pathway. Female mice treated with the GABA analogue pregabalin succumbed to disease earlier, consistent with our previous observation that gMDSCs have a central role in GBM progression in females. In contrast, pregabalin treatment had no effect in male mice with tumors or immunocompromised female mice. Assessment of the antiviral response signature revealed that GABA upregulates nitric oxide synthase 2 (NOS2) expression in gMDSCs. Correspondingly, the tumor-accelerating effect of pregabalin was diminished in NOS2 KO female mice. Collectively, these results identify a neuron-immune-cancer communication axis and indicate that GABA alters anti-tumor immune response in a sex-specific manner. These results support the future assessment of GABA pathway inhibitors as potential immunotherapy agents. VeloSano Philanthrophic Funds