Androgen loss weakens anti-tumor immunity and accelerates brain tumor growth 3761

Abstract Description Many cancers, including glioblastoma (GBM), exhibit a male-biased incidence and outcome disparity, partially driven by sex hormones. While androgens are known to suppress anti-tumor T cell immunity in certain solid tumors, we found that androgens instead enhance anti-tumor immunity in brain tumors. Upon castration, tumor growth was accelerated in brain tumor models, while the opposite effect was observed for tumors located outside the brain. Decreased T cell function was observed in both tumors and peripheral lymphoid organs in castrated mice, indicated by reduced anti-tumor cytokines and increased T cell exhaustion. Mechanistically, this systemic immunosuppression was driven by hyperactivation of the hypothalamus-pituitary-adrenal (HPA) axis in castrated mice with brain tumors. Blocking glucocorticoid receptors reversed the accelerated tumor growth in these mice, confirming the role of HPA axis dysregulation. This mechanism was brain-specific rather than GBM-specific, as hyperactivation of the HPA axis was also observed with intracranial implantation of non-GBM tumors. Furthermore, elevated production of proinflammatory cytokines (IL-1β, TNF) in the brain of castrated mice was identified as a driver of HPA axis activation. Taken together, these findings reveal unique endocrine-mediated mechanisms by which brain tumor modulate systemic immunity in the androgen-deprived setting and highlight the importance of organ-specific effects of anti-tumor immunity. Funding Sources NIH P01CA245705; NIH R35NS127083; American Brain Tumor Association; Cleveland Clinic; Case comprehensive cancer center Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)