Abstract
A sex difference in the incidence and outcome of patients with glioblastoma (GBM), the most common primary malignant brain tumor, has been well established, as male patients experience a worse prognosis. However, the contribution of sex hormones to anti-tumor immunity has not been fully explored. To test this, we orthotopically implanted syngeneic mouse GBM cells into male mice after castration or sham surgery to assess survival differences. Castrated immune-competent mice succumbed to tumors significantly faster than the sham surgery group, and this was rescued by exogenous testosterone administration. This finding was further corroborated by that blockade of androgen signaling using enzalutamide reproduced the effect of castration with shortened survival. In contrast, castration on immunocompromised mice, NSG and RAG1KO, resulted in no survival difference compared to sham animals, suggesting a role for immune system. Flow cytometry analysis of tumor-infiltrating immune cells revealed decreased cytokine production in T and NK cells from castrated mice, while no difference was found in immune cell infiltration. Flank tumor experiments suggested brain-specific regulation of T cell recruitment, as tumor growth was delayed in castrated mice with increased infiltration of CD8+ T cell. It is noted that decreased cytokine production in T cells and NK cells was observed in tumor as well as lymph nodes from flank tumor model. Surprisingly, mass spectrometry of serum revealed upregulated levels of circulating corticosterone in castrated mice regardless of tumor presence, suggesting that castration may induce systemic immunosuppression and regulate T cell infiltration to brain via upregulation of glucocorticoids. Taken together, our data demonstrate that testosterone regulates T cell immunity, possibly via glucocorticoids, and ultimately affects GBM tumor growth. Given the decreased level of testosterone in aged males with higher risk of GBM, these findings further suggest the potential therapeutic intervention of testosterone in GBM.