by Newswise — Transvaccenic acid (TVA), a long-chain fatty acid found in the meat and dairy products of grass-fed animals such as cows and sheep, improves CD8 capacity.+ T cells can infiltrate tumors and kill cancer cells, according to a new study by researchers at the University of Chicago.
The research, published this week in Naturealso shows that patients with higher levels of circulating TVA 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 trying to decipher the link between diet and human health, and it is very difficult to understand the underlying mechanisms due to the wide variety of foods people eat. But if we focus only on nutrients and metabolites derived from food, we begin to see how they influence physiology and pathology,” said Jing Chen, PhD, Janet Davison Rowley Distinguished Service Professor of Medicine at UChicago and one of the authors. main points of the new study. “By focusing on nutrients that can activate T cell responses, we found one that actually enhances antitumor immunity by activating an important immune pathway.”
Find nutrients that activate immune cells
Chen’s lab focuses on understanding how metabolites, nutrients and other molecules circulating in the blood influence cancer development and response to cancer treatments. For the new study, two postdoctoral fellows, Hao Fan, PhD, and Siyuan Xia, PhD, both co-authors, started with a database of about 700 known metabolites that come from foods and assembled a library of “blood nutrient” compounds. consisting of 235 bioactive molecules derived from nutrients. They screened compounds from this new library for their ability to influence antitumor immunity through CD8 activation.+ T cells, a group of immune cells essential for killing cancer or virus-infected cells.
After the scientists evaluated the six leading candidates in both human and mouse cells, they saw that TVA performed the best. TVA is the most abundant trans fatty acid present 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 carried out a series of experiments using cells and mouse models of various types of tumors. 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. The TVA diet also improved CD8 capacity+ T cells to infiltrate tumors.
The team also performed a series of molecular and genetic analyzes to understand how TVA affected T cells. These included a new technique for monitoring single-stranded DNA transcription called ketoxal-assisted single-stranded DNA sequencing, or KAS-seq, developed by Chuan He, PhD, John T. Wilson Distinguished Service Professor of Chemistry at UChicago and another senior author of the study. These additional assays, conducted by the Chen and He labs, showed that TVA inactivates a cell surface receptor called GPR43 that is typically activated by short-chain fatty acids often produced by the gut microbiota. TVA overpowers these short-chain fatty acids and activates a cell signaling process known as the CREB pathway, which is involved in a variety of functions including cell growth, survival, and differentiation. The team also showed that mouse models in which the GPR43 receptor was deleted exclusively from CD8+ The T cells also lacked their enhanced ability to fight tumors.
Finally, the team also worked with Justin Kline, MD, professor of medicine at UChicago, to analyze blood samples taken from patients undergoing CAR-T cell immunotherapy treatment for lymphoma. They saw that patients with higher levels of TVA tended to respond better to treatment than those with lower levels. They also tested leukemia cell lines working with Wendy Stock, MD, Anjuli Seth Nayak Professor of Medicine, and saw that TVA improved the ability of an immunotherapy drug to kill leukemic cells.
Focus on nutrients, not food
The study suggests that TVA could be used as a dietary supplement to aid in various T cell-based cancer treatments, although Chen notes that it is important to determine the optimized amount of the nutrient itself, not the food source. There is growing evidence about the detrimental health effects of excessive consumption of red meat and dairy, so this study should not be taken as an excuse to eat more cheeseburgers and pizza; rather, it indicates that nutritional supplements like TVA could be used to promote T cell activity. Chen believes there may be other nutrients that can do the same.
“There is early data showing that other plant fatty acids signal through a similar receptor, so we think there is a high possibility that plant nutrients could do the same by also activating the CREB pathway,” he said. .
The new research also highlights the promise of this “metabolomic” approach to understanding how building blocks of the diet affect our health. Chen said his team hopes to build a complete library of nutrients circulating in the blood to understand their impact on immunity and other biological processes such as aging.
“After millions of years of evolution, there are only a couple hundred food-derived metabolites that end up circulating in the blood, which means they might have some importance in our biology,” Chen said. “Seeing that a single nutrient like TVA has a very specific mechanism in a specific immune cell type, with a very profound physiological response at the whole organism level, I find really surprising and intriguing.”
The study “Transvaccenic acid reprograms CD8+ T Cells and Antitumor Immunity,” was supported by the National Institutes of Health (grants CA140515, CA174786, CA276568, 1375 HG006827, K99ES034084), a Pilot Project Award from the UChicago Division of Biological Sciences, the UChicago Ludwig Center, the Sigal Fellowship in Immunoncology, Margaret E. Early Medical Research Trust, the AASLD Foundation, a Harborview Foundation Endowment Fund, and the Howard Hughes Medical Institute.
