The Key Role of NAD+ in Anti-Tumor Immune Response: An Update

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an important molecule that functions as a co-enzyme in numerous metabolic processes. Generated both through de novo synthesis and via salvage pathways, NAD+ is the substrate for a variety of NAD+-consuming enzymes. Among them is CD38, a cell surface ecto-enzyme widely expressed on different types of cells and endowed with the function of cADP-ribose synthases/NAD+ glycohydrolase. Surface CD38 expression is increased in different hematological and solid tumors, where it cooperates with other ecto-enzymes to produce the immunosuppressive molecule adenosine (ADO). Few studies have explored the correlation of NAD+ levels with T-cell mediated anti-tumor response in preclinical models. We therefore discuss these novel findings, examining the possible contribution of NAD+ depletion, along with ADO production, in the immunosuppressive activities of CD38 in the context of human tumors. Lastly, we discuss the use of pharmacological inhibitors of CD38 and supplementation of different NAD+ precursors to increase NAD+ levels and to boost T cell responses. Such molecules may be employed as adjuvant therapies, in combination with standard treatments, for cancer patients.

The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

“…We identified a role of cADPR to promote cell progression by inducing cytoplasmic calcium flux via TRPM2 channel. Consistent with our study, F. Morandi concluded that inactivation of the CD38-cADPR axis might serve as a novel therapeutic intervention in lung cancer and a recent report indicated that TRPM2 was linked with poor prognosis in patients with pancreatic ductal adenocarcinoma [ 34 , 35 ]. In addition, to understand if the promotion of cADPR on tumor proliferation, and migration was a generalized phenomenon, we also demonstrated that cADPR could promote cell proliferation and migration in variety of human cell lines which existed the expression of TRPM2.…”

Functional assessment of the cell-autonomous role of NADase CD38 in regulating CD8+ T cell exhaustion

“…In addition, it is worth noting that the decrease of NAD + levels in CD8 + TILs is not solely regulated by CD38, which deficiency may compensate for upregulating the expression of other NADase. Notably, intracellular NAD + levels are highly coordinated by the consumption processes and biosynthesis, such as de novo synthesis and salvage pathways ( Morandi et al., 2021 ). Recently, Wang et al.…”

Dihydronicotinamide Riboside Is a Potent NAD+ Precursor Promoting a Pro-Inflammatory Phenotype in Macrophages

“…Thus, a potential therapeutic opportunity to increase the macrophage inflammatory phenotype may be to switch TAMs back to an M1 phenotype (45,46), highlighting the importance of understanding the mechanisms regulating macrophagemediated inflammation. Additionally, it is important to understand the role of different NAD + precursors in boosting T cell responses, as an alternative way to promote antitumor responses (47). In support of this hypothesis, it was recently shown that the CD38-NAD + -Sirt1 axis regulates immunotherapeutic anti-tumor T cell responses (48).…”