Increased NAD+ Promotes Sensitivity to Anti-Cancer Therapy

All cells need nicotinamide adenine dinucleotide (NAD+), a bioenergetic molecule, to carry out essential functions and for survival. But NAD+ production (biosynthesis) is often elevated in human cancers, where it plays a critical role in the initiation, progression, and relapse of tumors. Yet, how NAD+ metabolism — the chemical reactions that make, process, and use NAD+ — plays a role in the regulation of tumor progression through its evasion of the body’s immune response has remained largely unknown.

Wang and colleagues from the Secondary Military Medical University in Shanghai, China, published a study in Cell Metabolism where they provided evidence for a cellular mechanism whereby NAD+ synthesis in cells promotes tumor progression. Their experiments showed that supplementation with the NAD+ precursor nicotinamide mononucleotide (NMN) increased NAD+ levels and improved the effectiveness of a therapeutic option for tumors resistant to immunotherapy, a cancer treatment that helps the immune system fight off tumors.

In their study, the researchers provided experimental evidence from mice that decreased levels of a key enzyme in the NAD+ biosynthesis pathway, NAMPT, led to enhanced activation of white blood cells that attack tumors called CD8⁺ T cells. The activation of these T cells facilitated their function to combat tumors. The reduction in the NAMPT enzyme levels was accompanied by reductions in cellular levels of NAD+, indicating that NAD+ metabolism controls the CD8⁺ T cell function against tumors.

Their data also showed that NAD+ metabolism can drive tumor evasion from the immune system by promoting levels of a protein on cancer cells called PD-L1. The presence of PD-L1 on the surfaces of cancer cells inhibits the function of T cells by binding to receptors on the T cell surface called PD-1. The interaction between PD-L1 on cancer cells and PD-1 on T cells leads to T cell exhaustion, which is when T cells lose their ability to kill cancerous cells from binding too many foreign particles from tumors, and evasion of the immune response by cancer cells. The team then found that more NAMPT in tumor cells correlated with higher levels of the PD-L1 protein found on the surfaces of cancer cells and a higher incidence of tumor evasion from the immune response.