Potentiating the anti-tumor response of tumor infiltrated T cells by NAD + supplementation

Abstract Tumor immunotherapies have provided clinical benefits, yet great potential remains for optimizing therapeutic effects. Here, we show that low NAD + levels restrict the function of tumor infiltrating T lymphocytes (TILs). TILs harvested from human ovarian tumor tissues showed decreased NAD + levels compared with T cells from paired peripheral blood samples. The combination of whole-genome CRISPR and large-scale metabolic inhibitor screens implicated the NAD + biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) is required for T cell activation. Further isotopic labeling and LC-MS studies confirmed that NAD + depletion suppressed mitochondrial energy biosynthesis in T cells. Excitingly, NAD + supplementation significantly enhanced the tumor cell-killing efficacy of CAR-T cells ex vivo , and extended animal survive in both adoptive CAR-T model and immune checkpoint blockade treatment models in vivo . This study demonstrates an over-the-counter nutrient supplement NAD + could robustly boost the efficacy of T cell-based immunotherapy and provides insights into the cellular basis of T cell metabolic reprogramming in treating cancers. One Sentence Summary NAD + supplementation during cancer immunotherapies significantly enhances T cell activation and tumor killing capacity.