The nutrient found in beef and dairy improves imm

Trans vaccinic acid (TVA), a long-chain fatty acid found in meat and dairy products from grazing animals such as cows and sheep, improves CD8⁺ T cells to infiltrate tumors and kill cancer cells, according to a new study by researchers from the University of Chicago.

The research, published this week in naturealso show that patients with higher levels of TVA circulating in the blood responded better to immunotherapy, suggesting that it may have potential as a nutritional supplement to complement clinical cancer treatments.

“There are many studies that try to understand the link between diet and human health, and it is very difficult to understand the underlying mechanisms because of the wide variety of foods that people eat. But if we focus on the nutrients and metabolites derived from food, we begin to see how they affect physiology and pathology,” said Jing Chen, PhD, the Janet Davison Rowley Distinguished Service Professor at UChicago and one of the senior authors of. the new study. “By targeting nutrients that can activate T cell responses, we found one that enhances anti-tumor immunity by activating an important immune pathway.”

Get nutrients that activate immune cells

Chen’s lab focuses on understanding how metabolites, nutrients and other molecules circulating in the blood affect cancer development and response to cancer treatments. For the new study, two postdoctoral fellows, Hao Fan, PhD and Siyuan Xia, PhD, the two co-first authors, started a database of about 700 known food-derived metabolites and assembled a “blood nutrient” compound library. consisting of 235. bioactive molecules derived from nutrients. They screened the compounds in this new library for their ability to influence anti-tumor immunity by activating CD8⁺ T cells, a group of immune cells that are critical for killing cancer cells or viral infections.

After the scientists evaluated the top six candidates in both human and mouse cells, they saw that TVA performed best. TVA is the most abundant trans fatty acid in human milk, but the body cannot produce it on its own. Only about 20% of TVA is broken down into other byproducts, leaving 80% circulating in the blood. “That means there must be something else it does, so we started working on it more,” Chen said.

The researchers then performed a series of experiments with cells and mouse models of different types of tumors. Feeding mice a diet enriched with TVA significantly reduced the tumor growth potential of melanoma and colon cancer cells compared to mice fed a control diet. The TVA diet also improved CD8 capacity⁺ T cells to infiltrate tumors.

The team also carried out a series of molecular and genetic analyzes to understand how TVA affected the T cells. These included a new technique to monitor single-stranded DNA transcription called ketoxal-assisted single-stranded DNA sequencing , or KAS-seq, developed by Chuan He, PhD, the John T. Wilson Distinguished Service Professor of Chemistry at UChicago and other senior. author of the study. These additional assays, performed by both the Chen and He labs, showed that TVA inactivates a receptor on the cell surface called GPR43 that is normally activated by short-chain fatty acids often produced by gut microbiota. TVA neutralizes these short-chain fatty acids and activates a cellular signaling process known as the CREB pathway, which is involved in a range of functions including cellular growth, survival and differentiation. The team also showed that mouse models in which the GPR43 receptor was removed exclusively from CD8⁺ T cells also lacked enhanced tumor fighting ability.

Finally, the team also worked with Justin Kline, MD, Professor of Medicine at UChicago, to analyze blood samples taken from patients receiving CAR-T cell immunotherapy treatment for lymphoma. They saw that patients with higher levels of TVA tended to respond to treatment better than those with lower levels. They also tested cell lines from leukemia by working with Wendy Stock, MD, Anjuli Seth Nayak Professor of Medicine, and saw that TVA improved the ability of an immunotherapy drug to kill leukemia cells.

Focus on the nutrients, not the food

The study suggests that TVA could be used as a dietary supplement to aid in various T-cell-based cancer treatments, although Chen points out that it is important to determine the optimal amount of the nutrient itself, not the food source. There is a growing body of evidence regarding the harmful health effects of eating too much red meat and dairy, so this study should not be taken as an excuse to eat more cheeses and pizza; rather, it shows that nutritional supplements like TVA could be used to promote T cell activity. Chen thinks there may be other nutrients that can do the same thing.

“There is early data showing that other fatty acids from plants signal through a similar receptor, so we believe there is a strong possibility that nutrients from plants can do the same thing by activating the CREB pathway as well,” he said.

The new research also highlights the promise of this “metabolic” approach to understanding how the building blocks of nutrition affect our health. Chen said his team hopes to build a comprehensive library of nutrients circulating in the blood to understand their effects on immunity and other biological processes such as aging.

“After millions of years of evolution, there are only a few hundred metabolites derived from food that circulate in the blood, which means they may have some importance in our biology,” Chen said. “To see that one nutrient like TVA has a very targeted mechanism on a targeted immune cell type, with a very profound physiological response at the level of the whole organism – that’s amazing and fascinating.”

The study, “Trans-vaccine acid reprograms CD8⁺ T cells and anti-tumor immunity,” supported by the National Institutes of Health (grants CA140515, CA174786, CA276568, 1375 HG006827, K99ES034084), UChicago Division of Biological Sciences Pilot Project Award, Ludwig Center at UChicago Fellowship. Immuno-oncology, the Margaret E. Early Medical Research Trust, the AASLD and Harborview Foundation Gift Fund, and the Howard Hughes Medical Institute.

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