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

• Published in: Nature communications Vol. 14; no. 1; pp. 735 - 18
• Main Authors: Zhao, Qingnan, Hu, Jiemiao, Kong, Lingyuan, Jiang, Shan, Tian, Xiangjun, Wang, Jing, Hashizume, Rintaro, Jia, Zhiliang, Fowlkes, Natalie Wall, Yan, Jun, Xia, Xueqing, Yi, Sofia F., Dao, Long Hoang, Masopust, David, Heimberger, Amy B., Li, Shulin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38/5; 38/91; 59; 631/250/1619/554; 631/250/580; 692/4028/67/1059/2325; 692/4028/67/1922; 82/1; 82/51; 82/80; Animals; Anticancer properties; Antitumor activity; Brain; Brain cancer; Brain tumors; CD69 antigen; CD8 antigen; CD8-Positive T-Lymphocytes; Chemokines; CXCR3 protein; Fibrinogen; Glioblastoma; Glioblastoma - therapy; Glioma; Glioma cells; Humanities and Social Sciences; Immunologic Memory; Immunological memory; Lymphocytes; Lymphocytes T; Memory cells; Memory T Cells; Mice; multidisciplinary; Neoplasm Recurrence, Local; Science; Science (multidisciplinary); T cell receptors; T-Lymphocytes - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36430-2

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. Glioblastoma is an aggressive type of cancer with poor patient prognosis. Here, the authors show that T cells armed with an FGL2-specific scFV can induce antitumour responses mediated by tissue-resident memory T cells in the brain.