Sex-biased T cell exhaustion drives differential immune responses in glioblastoma.

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunological sex differences are not fully understood. Here, we demonstrate T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD1 treatment. Moreover, increased T cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by X chromosome inactivation escape gene Kdm6a. These findings demonstrate sex-biased pre-determined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response.