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Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy. Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.
Introduction
Glutathione (GSH) is the most abundant antioxidant that maintains cellular redox homeostasis. De novo synthesis of GSH is coordinated by the sequential actions of glutaminase, γ-glutamatecysteine ligase, and GSH synthetase, as well as regeneration from glutathione disulfide (GSSG) by glutathione disulfide reductase (GSR) (1). GSH is oxidized to GSSG through glutathione peroxidases (GPXs) to buffer reactive oxygen species (ROS). The ratio of GSH to GSSG decreases with exposure to oxidative stress (2, 3), and an imbalance in the GSH/GSSG ratio has been documented in a variety of disorders, such as cancer, neurodegenerative diseases, and viral infections (4). Indeed, high levels of GSH are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis, an irondependent programmed cell death (5). Therefore, targeting GPX4 (6, 7) and/or GSH synthesis (8) to induce cancer cell ferroptosis has become an attractive means for cancer therapy (9).
Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness (10-15). Histologically, T lymphocyte activation (16) and proliferation (17) are directly dependent on intracellular GSH availability. Previous studies have shown that GSH biosynthesis is required for inflammatory T cell responses (18, 19) and regulatory T cell suppressive function (20). Moreover, optimal CD8+...