TMIC-46. Androgen loss weakens anti-tumor immunity and accelerates brain tumor growth

Abstract Many cancers, including glioblastoma (GBM), have a male-biased sex difference in incidence and outcome. The underlying reasons for this sex bias are unclear but likely involve differences in the immune response, partly driven by sex hormones. Androgens have been shown to inhibit anti-tumor T cell immunity and promote tumor progression in melanoma and bladder cancer. However, we observed an unexpected tumor-suppressive mechanism of androgens in brain tumors. In murine brain tumor models, we found that castration accelerated intracranial tumor growth, whereas the opposite effect was observed when tumors were located outside the brain. Similar effects were observed in male GBM patients where testosterone treatment significantly reduced the risk of death. Decreased T cell function was observed in both tumors and peripheral lymphoid organs in castrated mice bearing brain tumors, 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, resulting in elevated glucocorticoid production. Blocking glucocorticoid receptors reversed the accelerated tumor growth in these mice, confirming the role of HPA axis dysregulation. Additionally, we found that glucocorticoid receptor signaling in myeloid cells was responsible for creating an immunosuppressive tumor microenvironment in castrated mice. 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, increased neuroinflammation was observed in the brains of castrated mice with brain tumors, characterized by elevated levels of proinflammatory cytokines that were also key mediators of HPA axis activation, including IL-1β and TNF, which were produced by microglia and when absent, rescued the aggressiveness induced by castration. Taken together, our findings demonstrate that brain tumors drive distinct neuroendocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.