Nrf2 as a negative regulator of CD8+ T-Cell-mediated anti-melanoma responses 3613

Abstract Description Melanoma is an aggressive form of skin cancer and a significant public health challenge in the United States, particularly due to the resistance of advanced-stage melanomas to standard therapies, emphasizing the need for novel treatment strategies. This study investigates the impact of Nrf2, an antioxidation protein, on the anti-tumor activity of CD8+ cytotoxic T-cells. Using a mouse model with T-cell-specific deletion of Keap1—a negative regulator of Nrf2, resulting in constitutively elevated Nrf2 levels (Nrf2-HI)—we found that Nrf2-HI CD8+ T-cells showed reduced expression of activation markers, inflammatory cytokines, and cytotoxic granules. Conversely, reducing Nrf2 levels in T-cells, either through T-cell specific deletion or by treatment with the Nrf2 inhibitor ML385 enhanced the killing capacity of T-cells against melanoma cells, in vitro. Furthermore, in B16F10 syngeneic mouse melanoma models, mice with Nrf2-KO T-cells developed smaller tumors and demonstrated longer survival, while mice with Nrf2-HI T-cells had larger tumors and shorter survival compared to wild-type controls. These findings suggest an inverse correlation between Nrf2 levels in CD8+ T-cells and their anti-melanoma tumor activity, identifying T-cell intrinsic Nrf2 as a potential negative regulator of anti-tumor immunity. Funding Sources AAI Careers in Immunology Fellowship Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)