IL-21 boosted stem-like memory characteristics in TET-deficient CAR-T cells 2887

Abstract Description Adoptive cell therapy (ACT) represents a novel approach to cancer treatment that employs genetically modified T cells, designated as chimeric antigen receptor T cells (CAR-T). The CAR-T cells are designed to effectively recognize and destroy cancer cells. Nevertheless, their efficacy is constrained in specific forms of blood cancer. A major limitation of CAR-T cell therapy for solid tumors is the challenge of ensuring their persistence and sustained activity within the body. TET enzymes, as key epigenetic modulators, play a critical role in CD8+ T cell differentiation and are central to regulating their responses to enhance anti-tumor immunity. The present study investigated the impact of TET deficiency on the memory function of CAR T cells, in addition to the role of IL-21 in orchestrating T cell differentiation and effector functions. In light of these findings, a novel strategy for treating solid tumors with genetically modified CAR-T cells was developed, which involved TET knockout and IL-21 administration. This intervention significantly increased the anti-tumor activity of CAR-T cells by improving their survival, expansion, and promotion of the less differentiated subtype. In conclusion, our approach, by inhibiting TET enzymes and promoting IL-21-mediated memory response, shows significant potential in enhancing CAR-T cell responses against solid tumors. This strategy offers promising new avenues for optimizing cancer immunotherapy. Funding Sources This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (RS-2023-00282907, Republic of Korea).” Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)