“During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM),” the article’s authors wrote.
“In parallel,” the scientists added, “redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4.
“During each of these fasting cycles, NK cells learned to use these fatty acids as an alternative fuel source to glucose,” she said.
This primed the NK cells to produce more interferon-gamma, a cytokine that plays an important role in antitumor responses.
Meanwhile, NK cells in the spleen were undergoing a separate reprogramming, making them better at using lipids as a fuel source.
A new study by researchers at Memorial Sloan Kettering Cancer Center (MSK) has found that in fasting mice, natural killer (NK) cells had their metabolisms “rewired.” Ultimately, the NK cells improved their ability to survive the rigors of the tumor microenvironment. Also, they fought cancer more effectively.
The MSK researchers presented their findings in Immunity. The study’s lead author is postdoctoral fellow Rebecca Delconte, PhD, and the senior author is Joseph Sun, PhD, an investigator in the MSK’s Immunology Program.
“During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM),” the article’s authors wrote. “NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism.”
The scientists observed that fasting-induced fatty acid oxidation was accompanied by increased expression of the enzyme CPT1A. To reinforce this association, the scientists deleted Cpt1a and found that doing so impaired NK cell survival and function.
“In parallel,” the scientists added, “redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production.”
The findings could help explain one of the mechanisms by which fasting may help the body defend against cancer—along with more generally reducing fat and improving metabolism. And while more research is needed, the results also suggest fasting could be a strategy to improve immune responses to make immunotherapy more effective, the study authors noted.
“Tumors are very hungry,” Sun pointed out. “They take up essential nutrients, creating a hostile environment often rich in lipids that are detrimental to most immune cells. What we show here is that fasting reprograms these natural killer cells to better survive in this suppressive environment.”
For the study, mice with cancer were denied food for 24 hours twice a week, and then allowed to eat freely in between fasts. This approach prevented the mice from losing weight overall, the authors noted. But these periods of fasting had a profound effect on NK cells.
Just as happens in humans, the mice saw a drop in their glucose levels and a rise in free fatty acids, which are lipids released by fat cells that can serve as an alternative energy source when other nutrients aren’t present, Delconte explained.
“During each of these fasting cycles, NK cells learned to use these fatty acids as an alternative fuel source to glucose,” she said. “This really optimizes their anticancer response because the tumor microenvironment contains a high concentration of lipids, and now they’re able enter the tumor and survive better because of this metabolic training.”
The fasting also led to a redistribution of NK cells within the body. Many of the NK cells traveled into the bone marrow, where, thanks to the fasting, they were exposed to high levels of a key signaling protein called interleukin-12. This primed the NK cells to produce more interferon-gamma, a cytokine that plays an important role in antitumor responses. Meanwhile, NK cells in the spleen were undergoing a separate reprogramming, making them better at using lipids as a fuel source.
“With both of these mechanisms put together, we find that NK cells are pre-primed to produce more cytokines within the tumor,” Delconte noted. “And with the metabolic reprogramming, they’re more able to survive in the tumor environment, and specialized to have improved anticancer properties.”
It’s unclear yet whether there are two separate populations of NK cells that get trained differently in different parts of the body, or whether the cells end up passing through both sites during their weeks-long life cycle.
“That’s the million-dollar question,” Sun remarked. “And one that we have only begun to answer using the cell-labeling techniques we used in this study.”
While human bone marrow samples weren’t studied as part of the project, the researchers noted that blood samples from cancer patients show that fasting causes a reduction of freely circulating NK cells in people, just as they observed in mice.
