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

Abstract

The dysfunction and clonal constriction of tumor-infiltrating CD8 + T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8 + T cell 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 + T cell metabolic and functional fitness. De novo NAD + synthesis is involved in CD8 + T cell 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 + T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD + regulates the CD8 + T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD + synthesis could restore CD8 + T cell metabolic fitness and antitumor function.

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