Loss of testosterone leads to impaired T cell function via glucocorticoids in mouse glioblastoma models

Abstract

Abstract While sex differences in glioblastoma (GBM) are well established, the contribution of sex hormones on these differences has not been fully explored. Recently, the immunoregulatory effect of testosterone in other type of cancers has been reported. To evaluate the effect of testosterone on GBM, we performed castration or sham surgery on mice, followed by intracranial implantation of syngeneic glioma cells. Surprisingly, the castrated B6 mice had more aggressive tumors compared to sham surgery controls and the castration induced aggressive tumor growth could be rescued by exogenous testosterone administration. This was further confirmed by chemical blockade of androgen receptor signaling using enzalutamide. In contrast, castration in Rag1KO mouse models did not show a survival difference compared to controls, suggesting a role for lymphocytes. Interestingly, upregulated levels of circulating corticosterone in castrated mice was detected by mass spectrometry, and glucocorticoid receptor blocker reversed the survival of castrated mice, suggesting glucocorticoid-mediated systemic immunosuppression upon castration. Flow analysis revealed decreased cytokine production in CD4+ and CD8+ T cells from tumors and lymph nodes in castrated mice. We also found that tumor growth was delayed in castrated mice when tumor cells were subcutaneously implanted in the flank while decreased cytokine production in T cells in tumor and lymph nodes from flank tumor model as well. These data suggest brain-specific effect of steroid hormone on tumor control. Taken together, our findings demonstrate that testosterone regulates T cell function via glucocorticoids, and ultimately affects GBM tumor growth in a site-specific manner. Supported by grants from NIH (R35 NS127083, P01 CA245705).