Lee, Juyeun

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)

Abstract Many cancers, including glioblastoma (GBM), exhibit a male-biased incidence and outcome disparity. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further influenced by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity in other solid tumors. Using a series of pre-clinical models, we observed that androgens drive anti-tumor immunity in brain tumors, contrasting with their effect in other tumor types. Upon castration, tumor growth was accelerated in GBM and brain tumor models, while the opposite effect was observed when tumors were located outside the brain. This castration effect could be reversed by testosterone administration. Flow cytometry revealed decreased T cell function, indicated by reduced anti-tumor cytokines (IFNγ and TNFα), and increased T cell exhaustion in both tumors and peripheral tissues in castrated mice, suggesting systemic immunosuppression. Indeed, the survival difference was completely abrogated in T cell deficient mice (RAG1 knockout). Mechanistically, increased hypothalamus-pituitary-adrenal (HPA) axis activity in castrated mice was responsible for the observed systemic immunosuppression, particularly in those with brain tumors. Blocking glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that elevated glucocorticoid signaling mediated the castration effect. 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. Neuroinflammation caused by brain tumors was stronger in castrated mice, and proinflammatory cytokines like IL-1 and TNF induced HPA axis hyperactivation. Together, these findings highlight that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.