Oxidative phosphorylation controls regulatory T cell suppressor activity of in the tumor microenvironment

Abstract Regulatory T cells (Tregs) are important elements of the tumor-associated immunosuppresive network. Here we show that Tregs in the tumor microenvironment are highly apoptotic. Although apoptotic Tregs express classical immunosuppressive proteins including PD-L1, CTLA-4, TGF-β and IL-35, blockade of these mediators does not abolish their suppressive effect. Apoptotic Tregs release a large amount of ATP and suppress T cell responses via adenosine A2A receptor. Furthermore, Tregs have higher mitochondrial load and their survival is associated with OxPhos and fatty acid β-oxidation. Apoptosis of Tregs leads to pannexin-1-dependent ATP release and provide a substrate for immunosuppression. The data support a novel notion that Tregs amplify their suppressor capacity via apoptosis and OxPhos may be a central metabolic pathway controlling Treg functionality in tumor.