Sex-specific T cell behavior drives differential immune responses in mouse glioblastoma models

Abstract

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor and has a median survival of 12–18 months with current standard-of-care of therapy. GBM sex differences in incidence and overall survival, with males experiencing a higher incidence and a worse prognosis compared to females. However, the role of immune cells in GBM sex differences outside of myeloid cells remains poorly understood. Using a syngeneic mouse GBM model, we recapitulated the sex differences observed in patients, with shortened survival in male hosts compared to female hosts. These findings were not recapitulated in immuno-deficient mouse strains such as NSG and RAG1KO mice, suggesting a role for immune cells, specifically T cells, in GBM sex differences. Flow cytometry analysis of tumor-infiltrating leukocytes revealed more T cells in female tumors, whereas male tumors were enriched in macrophages. Additionally, more T cells in male tumors exhibited high levels of inhibitory receptors, whereas most female T cells were more functional as measured by expression of anti-tumor cytokines such as TNF, IFN-gamma, and granzyme B. A bone marrow chimera model revealed that male T cells retained their phenotype in female hosts, whereas female T cell behavior was affected by the male environment. Furthermore, female T cells are more proliferative, with elevated expression of integrins compared to male T cells. Lastly, we found that males have more progenitor exhausted T cells, which led to better response to anti-PD1 treatment. Collectively, these results suggest that both cell-intrinsic and cell-extrinsic factors regulate T cell activity in a sex-specific manner, providing insights to develop sex-specific therapeutic approaches. Supported by grant from NIH (P01 CA245705)