Nutrients found in beef and dairy products improve the immune system

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

Research published this week NatureIt also shows that patients with higher levels of circulating TVA respond better to immunotherapy; this suggests that it may have potential as a nutritional supplement complementary to clinical treatments for cancer.

“There are many studies trying to unravel the link between diet and human health, and understanding the underlying mechanisms is very difficult due to the wide variety of foods people eat. But if we focus solely on the nutrients and metabolites derived from food, we begin to see how they influence physiology and pathology,” said Jing Chen, the Janet Davison Rowley Distinguished Service Professor of Medicine at UChicago and one of the senior authors of the new study. “By focusing on nutrients that can activate T-cell responses “We found a nutrient that actually boosts anti-tumor immunity by activating an important immune pathway.”

Finding nutrients that activate immune cells

Chen’s lab focuses on understanding how metabolites, nutrients, and other molecules circulating in the blood affect the development of cancer and the response to cancer treatments. For the new study, two postdoctoral researchers, Hao Fan, PhD, and Siyuan Xia, PhD, both co-authors, started with a database of nearly 700 known metabolites from foods and created a “blood nutritional” compound library of 235 substances. Bioactive molecules obtained from foods. They screened the compounds in this new library for their ability to affect anti-tumor immunity by activating CD8.⁺ T cells are a group of immune cells that are critical for killing cancerous or virus-infected cells.

After evaluating the top six candidates in both human and mouse cells, the scientists found 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 20% of TVA is broken down into other byproducts and 80% remains circulating in the blood. “That meant there had to be something else he was doing, so we started working on it more,” Chen said.

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

The team also performed a series of molecular and genetic analyzes to understand how TVA affects T cells. Among these was a new technique for monitoring the transcription of single-stranded DNA, called ketoxal-assisted single-stranded DNA sequencing, or KAS-seq, developed by Chuan He, the John T. Wilson Distinguished Service Professor of Chemistry at UChicago and another senior. author of the study. These additional analyzes by both the Chen and He laboratories showed that TVA inactivated a receptor on the cell surface called GPR43, which is usually activated by short-chain fatty acids produced by the gut microbiota. TVA inactivates these short-chain fatty acids and activates a cellular signaling process known as the CREB pathway, which is involved in a variety of functions such as cellular growth, survival, and differentiation. The team also showed that there are mouse models in which the GPR43 receptor is removed only from CD8.⁺ The T cells also lacked enhanced tumor-fighting abilities.

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

Focus on nutrients, not nutrients

The study suggests that TVA could be used as a nutritional supplement to assist with various T-cell-based cancer treatments; However, Chen points out that it is important to determine the optimized amount of the nutrient itself, not the nutrient source. There is growing evidence of the harmful health effects of consuming too much red meat and dairy; Therefore, this study should not be taken as an excuse to eat more cheeseburgers and pizza; rather, it indicates that nutritional supplements such as TVA can be used to support T cell activity. Chen thinks there may be other foods that can do the same thing.

“There is early data showing that other fatty acids from plants also signal through a similar receptor, so we believe it is likely that nutrients from plants may do the same by activating the CREB pathway,” he said.

The new research also highlights the promise of this “metabolomics” approach to understanding how the building blocks of diet affect our health. Chen said his team hopes to create a comprehensive library of blood-circulating nutrients 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 and circulating in the blood, which means they may have some importance in our biology,” Chen said. “To see that a single nutrient like TVA has a very targeted mechanism on a targeted immune cell type and has such a profound physiological response at the whole organism level, I find that really surprising and intriguing.”

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

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