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

Morandi, Fabio; Horenstein, Alberto L.; Malavasi, Fabio

doi:10.3389/fimmu.2021.658263

Cited by 19 publications

(10 citation statements)

References 37 publications

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“…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.…”

Section: Discussionsupporting

confidence: 90%

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

Gao

Liu

et al. 2021

Cell Death Dis

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It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

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Section: Discussionsupporting

confidence: 90%

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

Gao

Liu

et al. 2021

Cell Death Dis

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Sun

Shen

et al. 2022

iScience

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Chini

Peclat²,

Gomez³

et al. 2022

Front. Immunol.

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Nicotinamide adenine dinucleotide (NAD) metabolism plays an important role in the regulation of immune function. However, a complete picture of how NAD, its metabolites, precursors, and metabolizing enzymes work together in regulating immune function and inflammatory diseases is still not fully understood. Surprisingly, few studies have compared the effect of different forms of vitamin B3 on cellular functions. Therefore, we investigated the role of NAD boosting in the regulation of macrophage activation and function using different NAD precursors supplementation. We compared nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and nicotinamide (NAM) supplementation, with the recently described potent NAD precursor NRH. Our results show that only NRH supplementation strongly increased NAD+ levels in both bone marrow-derived and THP-1 macrophages. Importantly, NRH supplementation activated a pro-inflammatory phenotype in resting macrophages, inducing gene expression of several cytokines, chemokines, and enzymes. NRH also potentiated the effect of lipopolysaccharide (LPS) on macrophage activation and cytokine gene expression, suggesting that potent NAD+ precursors can promote inflammation in macrophages. The effect of NRH in NAD+ boosting and gene expression was blocked by inhibitors of adenosine kinase, equilibrative nucleoside transporters (ENT), and IκB kinase (IKK). Interestingly, the IKK inhibitor, BMS-345541, blocked the mRNA expression of several enzymes and transporters involved in the NAD boosting effect of NRH, indicating that IKK is also a regulator of NAD metabolism. In conclusion, NAD precursors such as NRH may be important tools to understand the role of NAD and NADH metabolism in the inflammatory process of other immune cells, and to reprogram immune cells to a pro-inflammatory phenotype, such as the M2 to M1 switch in macrophage reprogramming, in the cancer microenvironment.

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

Cited by 19 publications

References 37 publications

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

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

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

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

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