Fasting prepares the immune system’s natural killer cells to better fight cancer

Periods of fast they reprogram the immune system’s natural killer cells to better fight cancer, according to a new study in mice led by researchers at Memorial Sloan Kettering Cancer Center (MSK).

The benefits of fasting

Fasting and other dietary regimens are increasingly being explored as ways to deprive cancer cells of the nutrients they need to grow and to make cancer treatments more effective.

Now a team of researchers at MSK’s Sloan Kettering Institute and their collaborators have demonstrated for the first time that fasting can reprogram the metabolism of natural killer cells, helping them survive the hostile environment in and around tumors, while also improving the their ability to fight cancer. capacity. The study, led by postdoctoral researcher Rebecca Delconte, Ph.D., was published in Immunity .

The findings could help explain one of the mechanisms by which fasting may help the body defend against cancer, as well as reducing fat more generally and improving metabolism. And while more research is needed, the findings also suggest that fasting could be a strategy for improving immune responses and making immunotherapy more effective, the study authors note.

“Tumors are very hungry,” says immunologist Joseph Sun, Ph.D., senior 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 to better survive in this suppressive environment.”

Natural killer cells, or NK cells for short, are a type of white blood cell 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 trigger a targeted response.

In general, the more NK cells present within a tumor, the better the prognosis for the patient.

For the study, cancer mice were denied food for 24 hours twice a week, and then allowed to eat freely between fasts. 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 as happens in humans, the mice noticed a drop in glucose levels and an increase in free fatty acids, which are lipids released from fat cells that can serve as an alternative energy source when other nutrients aren’t present, says Dr. Delconte. .

“During each of these fasting cycles, the NK cells learned to use these fatty acids as an alternative fuel source to glucose,” he says. “This really optimizes their anti-tumor response because the tumor microenvironment contains a high concentration of lipids and now they are able to enter the tumor and survive better thanks to this metabolic training.”

Fasting also led to a redistribution of NK cells within the body, the researchers noted.

Many of the NK cells traveled to the bone marrow, where, thanks to fasting, they were exposed to high levels of a key signaling protein called Interleukin-12. This triggered NK cells to produce more interferon gamma, a cytokine that plays an important role in anti-tumor responses.

Meanwhile, NK cells in the spleen were undergoing separate reprogramming, making them more capable of using lipids as a fuel source.

“Putting both of these mechanisms together, we find that NK cells are pre-primed to produce more cytokines within the tumor,” says Dr. Delconte. “And with metabolic reprogramming, they are better able to survive in the tumor environment and specialize to have enhanced anti-tumor properties.”

It is not yet clear whether there are two separate populations of NK cells that are trained differently in different parts of the body or whether the cells end up passing through both sites during their weeks-long life cycle.

“This is 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 human bone marrow samples were not studied as part of the project, the researchers note that blood samples from cancer patients show that fasting causes a reduction in freely circulating NK cells in people, just as observed in mice.

There are several potential opportunities to advance mouse model research toward the clinic, the researchers say. First, clinical trials are already beginning to study the safety and effectiveness of fasting in combination with existing standard treatments.

Another avenue would be to identify drugs that could target the underlying mechanisms without requiring patients to fast. Third, NK cells could be put into a fasted state outside the body and then administered to enhance the effects of the treatment.

At this time, however, more clinical data on the effects of fasting on people with cancer are still needed, says Neil Iyengar, MD, a breast oncologist at MSK and a leading researcher on diet, metabolism and cancer, who was not directly involved in the study. study.

“There are many different types of fasting, and some might be beneficial while others might be harmful,” he says. “Patients should talk to their doctors about what is safe and healthy for their individual situation.”

An important step towards fasting-based therapies

Previous studies have shown how fasting can influence the immune system to improve several chronic inflammatory conditions, but little is known about how immune responses might drive a healthy metabolism. Because the liver is a central hub and regulator of metabolism, a group of researchers focused on understanding how liver cells and immune cells present in the liver communicate with each other under fasting conditions.

The study was a joint effort by Helmholtz Munich, the University of Ulm, the Technical University of Munich (TUM), the German Center for Diabetes Research (DZD), Heidelberg University Hospital and the University of Southern Denmark.

The researchers scanned the DNA of liver cells and immune cells, examining which parts of their DNA were active and which messenger molecules were released as a result. Their results demonstrated that these cells communicated with each other and highlighted the role of a molecule that is expressed in almost all cells of our body, namely the glucocorticoid receptor. “We found that in immune cells this receptor in particular allowed cross-communication between cell types during fasting.

By eliminating the receptor only in immune cells, we observed a disruption of fasting signals in liver cells. This means that immune cells are able to directly influence the effect of fasting on our metabolism,” says Anne Loft of Helmholtz Munich.

Giorgio Caratti and Jan Tuckermann of the University of Ulm add that “indeed, this is the first time we have seen this process under ‘healthy’ conditions. We knew that immune responses could affect our metabolism in an unhealthy environment, but this was new. This demonstrates that a low level of immune activity, or inflammation, is necessary for a balanced metabolic response to fasting.”

“Voluntary fasting has been shown to be beneficial for the prevention of a number of human metabolic diseases, including type 2 diabetes and obesity. The increase in people suffering from more than just these metabolic diseases is staggering and shows no signs of slowing. Our results serve to understand the molecular mechanisms underlying these diseases and could ultimately lead to the development of effective fasting-based therapies,” says Stephan Herzig who led the study at Helmholtz in Munich.