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