Targeting ROS-sensing Nrf2 enhances the efficacy of CAR-T cells in solid breast tumor model 4718

Abstract Description The cytotoxic T lymphocytes play a crucial role in cancer rejection; however, they encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although elevated levels of reactive oxygen species (ROS) in the hostile TME attenuate T cell function, the underlying molecular mechanism remains poorly understood. Nuclear factor-erythroid 2-related-2 (Nrf2) is activated by ROS and increases susceptibility to cancer progression; therefore, we hypothesized that high ROS levels might regulate anti-tumor responses of CD8 T cells through Nrf2 responses. Here, we demonstrated that T cell depletion significantly controlled and reversed tumor growth in Nrf2-deficient mice. Nrf2 expression is increased in tumor-infiltrating T cells. The Nrf2 deficiency in CD8 T cells augments the in vivo functional properties of CD8 T cells in a murine solid tumor model. Nrf2-deficient CD8 T cells are resistant to ROS, and their effector functions are sustained in ROS-rich TME. In addition, Nrf2 knockdown in human chimeric antigen receptor-expressing T cells enhanced the survival and functional activity of those cells in a humanized solid breast cancer model and effectively controlled tumor growth. Our findings provide novel insights into the mechanisms by which immune response and oxidative stress are integrated with tumor cells, and we highlight the significance of Nrf2 as a potential target for T cell immunotherapy to effectively control tumor growth in ROS-rich solid TME. Funding Sources Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, & Future Planning (2023R1A2C2002435) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)