FGL2-targeted T cells induced tumor-specific brain resident TRM cells preventing glioblastoma recurrence

Abstract Tissue-resident memory T cells (TRM) specific to previously encountered pathogens have been characterized, but tumor-specific TRM cells in brain have not been reported in the literature. We discovered that T cells armed with FGL2-blocking single-chain variable fragments (T-αFGL2) are able to induce tumor-specific CD8+TRM cells, which prevent glioblastoma recurrence, a major obstacle in achieving long term survivors. These tumor-specific CD8+TRM displayed a unique highly expanded T cell receptor repertoire distinct from that found in peripheral tissues. Notably, these CD8+TRM cells could be transplanted into the brains of either immunocompetent or T cell deficient naïve mice, transforming them to become immune reactive to tumor cells. The mechanism study found T-αFGL2 therapy boosted CD69+CD8+ memory T cells population in tumor bearing brains, which depend on CXCL9/10-CXCR3 signaling. These findings are the first to show tumor-specific brain resident CD8+TRM generation via adoptive cellular treatment and may have promising implications for cancer immunotherapy.