*For medical professionals only
Fasting against the effects of tumor immunity, which in turn involves another type of immune cell.
Recently, a research team led by Joseph C. Sun and Rebecca B. Delconte of Memorial Sloan-Kettering Cancer Center (MSKCC) published an important study in the prestigious journal Immunology [1].
For the first time, they found that fasting enhances anti-tumor abilities in mice by remodeling natural killer (NK) cells. Specifically, fasting mainly improves the anti-tumor strength of NK cells from two aspects: on the one hand, it promotes the return of NK cells in peripheral tissues and blood to the bone marrow, and strengthens the ability to release cytokine IFN-γ; On the other hand, it will also remodel the metabolism of NK cells in the spleen, so that these NK cells can acquire the ability to metabolize fatty acids and are more suitable for survival in the inhibitory microenvironment of tumors.
▲ Screenshot of the first page of the paper
There has been a lot of basic research on the relationship between fasting and health.
Among them, the relationship between fasting and cancer should be the most concerned, and some basic and clinical studies have preliminarily found that fasting has the potential to enhance anti-tumor immunity [2]. However, the mechanism by which fasting affects the immune system and thus regulates the anti-tumor immune response is still poorly understood.
As an immunologist who studies NK cells, Joseph C. Sun led his team to explore the mechanism by which fasting affects anti-tumor immunity, starting with NK cells.
They first developed a cyclic fasting diet (CFD) that lasted three weeks, with no weight loss and increased resistance to colon cancer (MC38) growth and melanoma (B16F10) metastasis compared to free-fed mice. They also found that the improvement of anti-tumor ability brought about by fasting is dependent on NK cells, and as long as NK cells are depleted, the ability of fasting to enhance anti-tumor response is greatly reduced.
▲ Fasting enhances anti-cancer immunity, NK cells are the key
After analyzing the NK cells infiltrated in the tumor, the researchers found that there was no significant change in the absolute number or maturity of NK cells within the tumor in the fasted mice compared to the free-dieted mice; There were no significant changes in a variety of immune cells, including CD8-positive T cells and dendritic cells. However, the anti-tumor ability of fasted mice is indeed enhanced, and it is dependent on NK cells.
So, what changes does fasting bring to NK cells?
It is well known that fasting can cause changes in the body's metabolism, such as a sharp decrease in serum glucose concentration, a significant increase in free fatty acid (FA) concentration, etc. SINCE ENERGY GAIN BY INNATE OR ADAPTIVE IMMUNE CELLS IS PRIMARILY DEPENDENT ON OXIDATIVE PHOSPHORYLATION OF GLUCOSE (OXPHOS), A DECREASE IN BLOOD GLUCOSE CONCENTRATION NECESSARILY AFFECTS BOTH OF THEM.
Sure enough, during a single acute fasting period, the glycolytic levels and glycolytic capacity of CD8-positive T cells and NK cells decreased significantly; However, to Joseph C. Sun's surprise, NK cells were able to maintain the ability of OXPHOS. SUBSEQUENT EXPERIMENTS HAVE FURTHER CONFIRMED THAT IN THE CASE OF A SINGLE ACUTE FASTING, NK CELLS CAN USE FATTY ACIDS AS RAW MATERIALS FOR OXPHOS, THUS ENSURING THEIR SURVIVAL. Since CD8-positive T cells do not have this ability, increased levels of apoptosis in CD8-positive T cells can be observed.
▲ NK cells from a single acute fasting mouse were able to maintain OXPHOS
Subsequently, Joseph C. Sun's team explored the effects of a three-week cyclic fasting diet (CFD) on NK cell metabolism.
They found that the spleen NK cells of mice on a cyclic fasted diet had an enhanced ability to take up fatty acids (FA) from the local environment, but did not experience lipid accumulation. In addition, genes related to fatty acid metabolism in NK cells are upregulated, such as the Cpt1a gene, which encodes a key enzyme for fatty acid metabolism. Expression of genes associated with glycolysis decreases.
At the gene expression level, there are a few genes that have caught the attention of researchers – genes induced by glucocorticoids (GCs). After treating NK cells in mice and humans with dexamethasone (Dex), they found that CPT1A expression levels were increased in both NK cells. This suggests that glucocorticoids such as dexamethasone can also induce fatty acid metabolism in NK cells, which was previously uncertain.
▲ Changes in the expression of some key genes
As we all know, the tumor microenvironment is a nutrient-deficient place, and cells that only get energy from glucose may not be able to survive in it.
The study by Joseph C. Sun's team also confirmed that NK cell CPT1A levels were elevated in tumors in mice on a cyclic fasting diet, as was increased absorption of fatty acids. NK cells with deletion of the Cpt1a gene are unable to control tumor growth even with a cyclic fasting diet. It is not difficult to see that the cyclic fasting diet allows Nk cells to acquire the ability to metabolize fatty acids, so that they can acquire the skills to survive in the tumor microenvironment, which is the key for NK cells to exert anti-tumor effects under fasting conditions.
In addition to the above effects, fasting has another effect on NK cells. Similar to previous studies, Joseph C. Sun's team also observed that mature NK cells in the blood and peripheral tissues reaggregated into the bone marrow during fasting. If NK cells are inhibited from entering the bone marrow, it weakens the antitumor effects mediated by a cyclic fasting diet. This suggests that the NK cells that "return" to the bone marrow acquire/enhance some anti-cancer skills.
The results showed that the ability of NK cells in the bone marrow of cyclic fasting diet mice to secrete anti-tumor cytokine IFN-γ was significantly increased.
▲ Schematic diagram of the mechanism
Overall, this study by Joseph C. Sun and Rebecca B. Delconte's team showed that fasting had different effects on NK cells at different tissue sites, enhancing NK cells' anti-tumor ability in at least two ways. On the one hand, it gives NK cells the ability to metabolize fatty acids in the spleen, making them more adaptable to the tumor microenvironment. On the other hand, it promotes the entry of peripherally mature NK cells into the bone marrow and enhances their ability to secrete IFN-γ.
It is understood that this is also the first time that scientists have discovered that fasting can remodel the metabolism of NK cells, thereby enhancing the anti-tumor ability of NK cells. As for the potential clinical value of this finding, the researchers believe that there are three: one is that it can guide current clinical research; The second is to find key targets that allow patients to reap the benefits without fasting; The third is that it may help improve the effectiveness of NK cell therapy. However, the researchers also caution patients to be cautious about fasting, as its clinical effects still need to be confirmed by clinical studies.
We look forward to the clinical translation of this research result.
Bibliography:
[1]. Delconte RB, Owyong M, Santosa EK, et al. Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity. Immunity. Published online June 12, 2024. doi:10.1016/j.immuni.2024.05.021
[2]. Vernieri C, Fucà G, Ligorio F, et al. Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer. Cancer Discov. 2022; 12(1):90-107. doi:10.1158/2159-8290.CD-21-0030
本文作者丨BioTalker