FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells

Although tissue-resident memory T (T_RM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain T_RM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8⁺ T_RM cells that prevent glioblastoma recurrence. These CD8⁺ T_RM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8⁺ T_RM cells reject glioma cells. Mechanistically, T-αFGL2 cell treatment increased the number of CD69⁺CD8⁺ brain-resident memory T cells in tumor-bearing mice via a CXCL9/10 and CXCR3 chemokine axis. These findings suggest that tumor-specific brain-resident CD8⁺ T_RM cells may have promising implications for the prevention of brain tumor recurrence.