Fasting periods reprogram the immune system's natural killer cells to better fight cancer, according to a new study in mice by researchers at Memorial Sloan Kettering Cancer Center (MSK).
Fasting and other nutritional regimens are increasingly being investigated as ways to deprive cancer cells of the nutrients they need to grow and make cancer treatments more effective.
Now, a team of researchers from MSK's Sloan Kettering Institute and their collaborators have shown for the first time that fasting can reprogram the metabolism of natural killer cells, allowing them to survive the harsh conditions in and around tumors, while also improving their cancer fighting ability. skill. The study, led by postdoctoral researcher Rebecca Delconte, PhD, was published June 14 Immunity.
The findings could help explain one of the mechanisms by which fasting may help the body defend itself against cancer – along with reducing fat and improving metabolism more generally. And while more research is needed, the results also suggest that fasting could be a strategy to improve immune responses to make immunotherapy more effective, the study authors note.
“Tumors are very hungry,” says immunologist Joseph Sun, PhD, senior author of the study. “They absorb essential nutrients, creating a hostile environment that is often rich in lipids that are harmful to most immune cells. What we show here is that fasting reprograms these natural killer cells to better survive in this oppressive environment.”
What are natural killer cells?
Natural Killer cells, or NK cells for short, are a type of white blood cells that can kill abnormal or damaged cells, such as cancer cells or cells infected with a virus. They get their name because they can destroy a threat without ever having encountered it before – unlike T cells, which require prior exposure to a specific enemy to mount a targeted response.
In general, the more NK cells there are 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, after which they were allowed to eat freely between fasting periods. This approach prevented the mice from losing weight overall, the authors note.
But these periods of fasting had a profound effect on NK cells.
Just like in humans, the mice saw a drop 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 no other nutrients are present, says Dr. Delconte. .
“During each of these fasting cycles, NK cells learned to use these fatty acids as an alternative fuel source to glucose,” she says. “This really optimizes their anti-cancer response because the tumor microenvironment contains a high concentration of lipids, and now they can penetrate the tumor and survive better thanks to this metabolic training.”
Fasting reprograms NK cells
Fasting also led to a redistribution of NK cells in the body, the researchers noted.
Many of the NK cells traveled to the bone marrow, where fasting exposed them to high levels of an important signaling protein called Interleukin-12. This caused the NK 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, improving their ability to use lipids as a fuel source.
“With both mechanisms brought together, we find that NK cells are pre-primed to produce more cytokines in the tumor,” says Dr. Delconte. “And thanks to the metabolic reprogramming, they are better able to survive in the tumor environment and specialize in enhanced anti-cancer properties.”
It is still unclear whether there are two separate populations of NK cells that are trained differently in different parts of the body, or whether the cells pass through both locations during their weeks-long life cycle.
“That's the million-dollar question,” says Dr. Sun. “And a question we have only just begun to answer using the cell labeling techniques we used in this study.”
Although human bone marrow samples were not examined as part of the project, the researchers note that blood samples from cancer patients show that fasting causes a reduction in free circulating NK cells in humans, just as they observed in mice.
Potential to improve cancer treatments
There are several potential avenues for bringing mouse model research to the clinic, the researchers say. First, clinical trials are already beginning to investigate the safety and effectiveness of fasting in combination with existing standard treatments. Another possibility would be to identify drugs that can address the underlying mechanisms without requiring patients to fast. Third, NK cells could be introduced into a fasting state outside the body and then administered to enhance treatment effects.
At this time, however, more clinical data are still needed on the effects of fasting for people with cancer, says Neil Iyengar, MD, an MSK breast oncologist and leading researcher in the fields of nutrition, metabolism, and cancer, who did not directly was involved in the development of cancer. study.
“There are many different types of fasting, and some can be helpful while others can be harmful,” he says. “Patients should talk to their doctors about what is safe and healthy for their individual situation.”
