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Targeting ROS-sensing Nrf2 in T cells potentiates anti-tumour responses
Abstract No. : 30

Category

Engineered T cell therapy (e.g., CAR/TCR-T)
The CD8⁺ cytotoxic T lymphocytes play a crucial role in cancer rejection; however, they encounter dysfunction and exhaustion in the immunosuppressive tumour microenvironment (TME). Although the reactive oxygen species (ROS)-rich environment attenuates the function of these cells, 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 hypothesised that high ROS levels might regulate anti-tumour responses of cytotoxic T lymphocytes through Nrf2 responses. Here, we demonstrated that T cell depletion significantly controlled and reversed tumour growth in Nrf2-deficient mice. Nrf2 expression is increased in tumour-infiltrating (TI) T cells. The Nrf2 deficiency in CD8+ T cells augments the in vivo functional properties of cytotoxic T lymphocytes in a murine solid tumour model. Nrf2-deficient CD8+ T cells are resistant to ROS, and their effector functions are sustained in a ROS-rich microenvironment. In addition, Nrf2 knockdown in human chimeric antigen receptor-expressing T cells enhanced the survival and functional activity of those cells in a humanised solid tumour model and effectively controlled tumour growth. Our findings provide novel insights into the mechanisms by which immune response and oxidative stress are integrated with tumour cells, and we highlight the significance of Nrf2 as a potential target for T cell immunotherapy to effectively control tumour growth in a ROS-rich solid TME.
#Nrf2
#Reactive oxygen species
#T cell immunotherapy
#CAR-T cells
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