Glioblastoma is an aggressive primary brain tumor with a highly immunosuppressive microenvironment that makes it very difficult to treat. Male individuals are more likely to develop the disease and have a worse prognosis than female patients. There is evidence that male and female patients also exhibit a differential immune response, but the underlying mechanisms are unclear.
Lee et al. now show that sex-biased T cell exhaustion is a key factor in the sex differences in glioblastoma. The authors profiled tumor-infiltrating immune cells in mice and found significantly higher levels of CD8+ T cells — which are important for immune surveillance — in females compared with males. However, this survival advantage was absent when CD8+ T cells were depleted in female mice before tumor implantation, which suggests that these T cells are a vital part of the sex differences in survival. The authors also found a significant increase in progenitor exhausted T (PEX) cells in the male CD8+ T cell population and an increase in effector cytokine production in female CD8+ T cells, which indicates that male T cells are exhausted more quickly than female T cells. PEX cells are known to respond to anti-PD-1 treatment and Lee et al. observed that survival was extended in male mice who received the treatment, compared with controls. Anti-PD-1 blockade reduced levels of exhausted T cells and increased the proliferation of male T cells compared with female T cells, which suggests that this treatment can effectively reinvigorate T cells in male tumors. Using bone marrow chimera and adoptive transfer models, the authors show that the regulation of T cell exhaustion is largely cell-intrinsic and mediated in part by the UTX protein (encoded by the Kdm6a X chromosome inactivation escape gene), which is more highly expressed in female T cells. Notably, the sex bias in T cell exhaustion was also observed in T cells from male patients with glioblastoma.
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