NAD+ has drawn attention to helping out the NK cells in the immune system. They are a group of lymphocytes that quickly react to pathological agents. They are most effective in destroying cells infected with viruses and in detecting and controlling early signs of malignant diseases. In addition, NK cells kill tumor cells without being previously activated (unlike cytotoxic T lymphocytes). When NK cells are activated, the NAD+ levels are increased too. How is NAD+ involved in the activity and viability of NK cells?
What are NK cells?
Natural killer cells (NK cells) control tumors and other infected cells. The primary goal of natural killer cells is to identify foreign substances that may threaten the body. Recognition and marking of that “enemy” lead to a series of biological processes that destroy the “enemy” cell.
In addition, NK cells secrete cytokines such as IFNγ and TNFα, which act on macrophages and dendritic cells to improve the immune response. NK cells are constantly in contact with other cells. Will the cell be attacked by NK cells depends on the balance of signals from activated receptors and inhibitory receptors on the surface of the NK cells. Most healthy cells have MHC I receptors on their surface, which signal that they are their cells; NK cells recognize them and do not attack them. Malignant and infected cells often lose their MHC I, so they can be destroyed by NK cells, which release cytotoxic granules, and leads to the lysis of those cells.
The key findings
A recent finding has investigated the connection between NAD+ and NK cells in tumor cells. The salvage pathway was essential when talking about how NAD+ activates NK cells. The salvage pathway maintains NAD+ levels in NK cell activation, thus maintaining mitochondrial homeostasis. In tumor-infiltrating NK cells (TINKs), the weakened NAD+ salvage resulted in a low patient survival rate. Therefore, NAD+ supplementation with NMN precursor significantly impacts the antitumor activity in both human and mouse NK cells.
To investigate if NAD+ can be used as possible NK-based immunotherapy in cancer cells, 36 tumor and para-tumor tissues were obtained from human hepatocellular carcinoma (HCC) patients. This study included all patients based on their diseases and no previous treatment.
The mice were injected with IL-2 every two days to observe NK activation in vivo, and tumor size in each mouse was monitored.
NAD+ promotes NK cells activation
During NK activation, the metabolism of NAD+ changes. Therefore, supplementation with NAD+ has positive effects on NK function and homeostasis. In addition, it was found that NAD+ supplementation improved the production of NF-α, IFN-γ, and perforins.
Guo, X., Tan, S., Wang, T., Sun, R., Li, S., Tian, P., … & Liang, X. NAD+ salvage governs mitochondrial metabolism invigorating NK cell antitumor immunity. Hepatology.
(The effects of NAD+ supplementation on several NK components.)
NAD+ supplementation also increased cytokine production and cytotoxicity, which resulted in enhanced viability and proliferation of NK cells. All these factors imply that NAD+ supplementation can positively impact NK homeostasis and function.
Guo, X., Tan, S., Wang, T., Sun, R., Li, S., Tian, P., … & Liang, X. NAD+ salvage governs mitochondrial metabolism invigorating NK cell antitumor immunity. Hepatology.
(Improved NK viability and proliferation, leading to better NK function and homeostasis.)
NAD+ salvage is responsible for optimal NK function
NAD+ is synthesized via three pathways: salvage, de novo, and Preiss–Handler. To investigate which NAD+ pathway is crucial for optimal NK function, the researchers measured NAD+ levels in mouse splenic NK cells treated with various NAD+ precursors for 16h of food restriction.
The results showed that NMN, used in the salvage pathway, significantly increased NAD+ levels. In contrast, the other precursors, quinolinic acid used in the de novo synthesis and nicotinic acid used in the PA pathway, showed no effects.
NMN supplementation also raises perforin levels, suggesting that the NAD+ salvage pathway is crucial for optimal NK function. In addition, NMN also improves energy metabolism and mitochondrial homeostasis of NK cells. This fact was supported by the analysis of NMN supplementation in splenic NK cells. NMN treatment recovered mitochondria dysfunction in NK cells and increased ATP levels. These results indicate that boosting NAD+ levels help in energy metabolism and mitochondrial homeostasis in NK cells.
Guo, X., Tan, S., Wang, T., Sun, R., Li, S., Tian, P., … & Liang, X. NAD+ salvage governs mitochondrial metabolism invigorating NK cell antitumor immunity. Hepatology.
(NMN increases NAD+ levels in mouse splenic NK treated.)
Guo, X., Tan, S., Wang, T., Sun, R., Li, S., Tian, P., … & Liang, X. NAD+ salvage governs mitochondrial metabolism invigorating NK cell antitumor immunity. Hepatology.
(NMN improves mitochondrial function in NK cells.)
NMN supplementation improves the antitumor activity of NK cells
Several experiments were done to answer this question. Giving NMN improved the antitumor activity of NK cells, leading to better survival in mice. Furthermore, in a mouse melanoma model, NMN treated group showed increased cytokine expression. Splenic NK cells were treated with and without NMN in the third group. NMN-treated NK cells suppressed the growth of the tumor, which means that NMN supplementation can be used as a possible treatment for NK cells’ antitumor immunity.
Guo, X., Tan, S., Wang, T., Sun, R., Li, S., Tian, P., … & Liang, X. NAD+ salvage governs mitochondrial metabolism invigorating NK cell antitumor immunity. Hepatology.
(NMN supplementation enhances the antitumor activity of NK cells.)
To sum up
NK cells can kill tumor cells and any other virus-infected cells. This study is focused on the correlation between NAD+ metabolism and NK cells. Cell metabolism plays a crucial role in better mitochondrial homeostasis and NK function. NMN supplementation improved the antitumor processes of NK cells. For that purpose, the salvage pathway uses NMN for NAD+ production and presents a significant increase in NAD+ levels.
Following these findings, we can conclude that NMN supplementation significantly raises NAD+ levels. NAD+ metabolism can support the antitumor activity of NK cell therapy.
References
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290424/
