De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function

Abstract

The dysfunction and clonal constriction of tumor-infiltrating CD8+ Tcells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ Tcell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ Tcell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ Tcell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ Tcell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ Tcell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ Tcell metabolic fitness and antitumor function.