Loss of testosterone activates HPA axis and induces systemic immunosuppression in glioblastoma

The inhibitory role of androgen on anti-tumor immunity has been recently highlighted. Given the male-biased incidence and poorer outcomes in glioblastoma (GBM), we investigated the role of androgen using GBM syngeneic mouse models. Subcutaneous injection of GBM cells resulted in delayed tumor growth in castrated male mice, in line with the findings in other tumors. However, intracranial injection of the same tumor cells led to shorted survival in castrated mice, which could be reversed by testosterone administration. We confirmed site-specific nature of this effect, as the intracranial implantation of non-brain tumor cells, such as melanoma and bladder cancer cells, recapitulated the shorter survival in castration mice. Flow analysis revealed decreased expression of anti-tumor cytokines such as IFNγ and TNFα in T cells from tumors and the periphery in castrated mice, suggesting systemic immunosuppression. Indeed, the survival difference was completely abrogated in RAG1KO mice. Mechanistically, serum glucocorticoid levels were increased in castrated mice, and its pharmacological blockade extended survival in castrated mice, but not in control mice. Finally, an increased activity of hypothalamus-pituitary-adrenal (HPA) axis was observed, augmented by loss of testosterone and the presence of brain tumors.  Taken together, these findings demonstrate that testosterone regulates HPA axis and systemic immune responses, ultimately affecting GBM growth in a site-specific manner.