Fasting and other eating patterns are increasingly being explored as methods of depriving cancer cells of the nutrients they need to grow, as well as improving the effectiveness of cancer treatments, and a new study by researchers at the Memorial Sloan Kettering Cancer Center (MSK) has shown for the first time that fasting can reprogram the metabolism of the immune system’s natural killer cells, helping them survive in the harsh environment of tumors and improving their ability to fight cancer.
The findings have been published in the journal Immunity and could help explain one of the mechanisms by which fasting can help the body defend against cancer, in addition to reducing fat and improving metabolism. Although the tests have been carried out in mice and more research is needed, the results also suggest that fasting could be a strategy to improve immune responses and make immunotherapy more effective, the study authors noted.
“Tumors are very voracious,” said immunologist Joseph Sun, lead author of the study. “They absorb essential nutrients creating a hostile environment, often rich in lipids that are harmful to most immune cells. “What we show here is that fasting reprograms these natural killer cells so that they survive better in this suppressive environment.”
How natural killer cells of the immune system work
Natural killer cells, or NK cells, are a type of white blood cell that can kill abnormal or damaged cells, such as cancer cells or cells infected by a virus. They are called ‘natural’ because they can destroy a threat without having encountered it first, unlike T cells, which require prior exposure to a specific enemy to mount a targeted response.
In general, the greater the number of natural killer cells present in a tumor, the better the prognosis for the patient. For the study, mice with cancer were deprived of food for 24 hours twice a week, and then allowed to eat freely between fasts. This approach prevented the mice from losing weight overall, according to the authors, but these periods of fasting had a profound effect on NK cells.
“During each of the fasting cycles the natural killer cells learned to use fatty acids as an alternative fuel source to glucose, which optimizes their response against cancer”
As in humans, the mice experienced a decrease in their glucose levels and an increase in free fatty acids, which are lipids released by fat cells that can serve as an alternative energy source when other nutrients are not present. explained Dr. Rebecca Delconte, who led the study.
“During each of these fasting cycles, the natural killer cells learned to use these fatty acids as an alternative fuel source to glucose,” he explained. “This really optimizes their anti-cancer response because the tumor microenvironment contains a high concentration of lipids, and now they can enter the tumor and survive better thanks to this metabolic training.”
An approach that could improve cancer treatments
Fasting also led to a redistribution of natural killer cells within the body, the researchers said. Many of the NK cells traveled to the bone marrow, where, thanks to fasting, they were exposed to high levels of a key protein called Interleukin-12. This primed the natural killer cells to produce more Interferon-gamma, a cytokine that plays an important role in anti-tumor responses. Meanwhile, NK cells in the spleen underwent separate reprogramming, making them better at using lipids as a fuel source.
“With these two mechanisms together, we found that natural killer cells are pre-primed to produce more cytokines within the tumor,” said Dr. Delconte. “And with metabolic reprogramming, they are better able to survive in the tumor environment and become specialized to have enhanced anti-cancer properties.”
It’s not yet clear whether there are two separate populations of natural killer cells that train differently in different parts of the body, or whether the cells end up passing through both sites during their several-week life cycle. “That’s the million-dollar question,” says Dr. Sun. “And one that we have only begun to answer using the cell labeling techniques we used in this study.”
Although no human bone marrow samples were studied as part of the project, the researchers note that blood samples from cancer patients show that fasting causes a reduction in freely circulating natural killer cells in people, just as they observed in mice. .
There are several potential opportunities to advance mouse model research toward the clinic, the researchers say. First, clinical trials are already underway to evaluate the safety and effectiveness of fasting in combination with available standard treatments. Another avenue would be to identify drugs that could target the underlying mechanisms without requiring patients to fast. Third, natural killer cells could be put into a fasting state outside the body and then administered to enhance the effects of the treatment.
