Metabolic reprogramming of antitumor CD8+ T cells by modulation of GSH-Gpx4 axis

Abstract

Abstract The CD8+ T cells within tumor microenvironment are the most essential component in tumor immunity. Activation of CD8+ T cells is coupled to various metabolic reprogramming. Glutathione (GSH) as the key role in oxidative metabolismto buffer increased reactive oxygen species (ROS) in activated T cells, is important for T cells effector functions in the context of inflammation. The function and mechanism by GSH metabolism in regulating anti-tumor immunity of CD8+ T cells remain unknown. Here, we show that GSH is dependent on glutathione peroxidase 4 (Gpx4) to maintain CD8+ T cell activity, and A2AR signaling pathway interacts with the GSH-Gpx4 axis to reprogram the metabolism and survival of functional CD8+ T cells. Interestingly, A2AR signaling blockade increases effector function of antitumor CD8+ T cells, but facilitates the assumption of intracellular GSH, leading to rapid ferroptosis. Notably, combination treatment with a potent ferroptosis inhibitor liproxstatin-1 (Lip-1) and A2AR antagonists elicits a synergistic antitumor efficacy and enhanced mitochondrial functionality of antitumor CD8+ T cells in multiple mouse tumor models. Finally, we generate a gene expression signature for GSH metabolism in tumor-infiltrating CD8+ T cells positively correlating with favorable clinical outcomes. Our work demonstrate a critical role of GSH metabolism in modulating antitumor CD8+ T cell survival and functionality, pointing to new strategies of targeting these cells for cancer immunotherapy.