Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor

Live regulatory T cells (T_reg cells) suppress antitumor immunity, but how T_reg cells behave in the metabolically abnormal tumor microenvironment remains unknown. Here we show that tumor T_reg cells undergo apoptosis, and such apoptotic T_reg cells abolish spontaneous and PD-L1-blockade-mediated antitumor T cell immunity. Biochemical and functional analyses show that adenosine, but not typical suppressive factors such as PD-L1, CTLA-4, TGF-β, IL-35, and IL-10, contributes to apoptotic T_reg-cell-mediated immunosuppression. Mechanistically, apoptotic T_reg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A_2A pathways. Apoptosis in T_reg cells is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor T_reg cells sustain and amplify their suppressor capacity through inadvertent death via oxidative stress. This work highlights the oxidative pathway as a metabolic checkpoint that controls T_reg cell behavior and affects the efficacy of therapeutics targeting cancer checkpoints.