The histone demethylase Utx controls CD8⁺ T-cell-dependent antitumor immunity via epigenetic regulation of the...

CD8⁺ T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8⁺ T cells. However, the role of Utx, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of Utx in effector CD8⁺ T-cell differentiation and the antitumor immune response. In a murine tumor-bearing model, an increased tumor size and decreased survival rate were observed in T-cell-specific Utx KO (Utx KO) mice compared with wild-type (WT) mice. The number of CD8⁺ T cells in tumor-infiltrating lymphocytes (TILs) was significantly decreased in Utx KO mice. We found that the acquisition of effector function was delayed and attenuated in Utx KO CD8⁺ T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in Utx KO effector CD8⁺ T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8⁺ T cells to tumor sites, was substantially decreased in Utx KO CD8⁺ T cells. These findings suggest that Utx promotes CD8⁺ T-cell-dependent antitumor immune responses partially through epigenetic regulation of the effector function.