Newswise - Trans-vaccenic acid (TVA), a long-chain fatty acid found in meat and dairy products from grazing animals such as cows and sheep, improves the ability of CD8+ T cells can infiltrate tumors and kill cancer cells, according to a new study from researchers at the University of Chicago.
The research, published this week in Nature Research also shows that patients with higher levels of TVA circulating in the blood responded better to immunotherapy, suggesting it could have potential as a nutritional supplement to complement clinical treatments for cancer.
"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 that people eat. But if we focus just on the nutrients and metabolites that come from food, we begin to see how they influence physiology and pathology," said Jing Chen, PhD, 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 one that actually improves anti-tumor immunity by activating a key immune pathway."
Finding nutrients that activate immune cellsChen's laboratory 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 from 235 bioactive molecules derived from nutrients. They screened the compounds in this new library for their ability to influence antitumor immunity by activating CD8+ T cells, a group of immune cells that are crucial for killing cancer cells or virally infected cells.
After the scientists evaluated the top six candidates in both human and mouse cells, they saw that TVA performed the best. TVA is the most common trans fatty acid in breast milk, but the body cannot produce it itself. Only about 20% of TVA is broken down into other byproducts, leaving 80% circulating in the blood. "That means there must be something else doing it, so we started working on it more," Chen said.
The researchers then conducted a series of experiments using cells and mouse models of different tumor types. 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 output+ T cells to infiltrate tumors.
The team also performed a series of molecular and genetic analyzes to understand how TVA affected T cells. These include a new technique for monitoring the transcription of single-stranded DNA, called kethoxal-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 another senior author of the study. These additional tests, conducted by both the Chen and He laboratories, showed that TVA inactivates a cell surface receptor called GPR43, which is normally activated by short-chain fatty acids often produced by the gut microbiota. TVA overpowers these short-chain fatty acids and activates a cellular signaling process known as the CREB pathway, which is involved in a variety of functions including cellular growth, survival and differentiation. The team also showed that mouse models in which the GPR43 receptor was deleted exclusively from CD8+ T cells also lacked their enhanced tumor-fighting ability.
Finally, the team also collaborated 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 TVA levels tended to respond better to treatment than patients with lower TVA levels. They also tested cell lines against leukemia by working with Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine, and saw that TVA improved an immunotherapy drug's ability to kill leukemia cells.
Focus on the nutrients, not the foodThe study suggests that TVA could be used as a dietary supplement to aid various T cell-based cancer treatments, although Chen points out that it is important to determine the optimized amount of the nutrient itself, and not the food source. There is mounting evidence about the harmful health effects of consuming too much red meat and dairy products, so 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 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 think there is a good chance that plant nutrients can 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 the building blocks of diet influence our health. Chen said his team hopes to build a comprehensive 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 few hundred metabolites from food that ultimately circulate in the blood, so that means they could be of 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, with a very profound physiological response at the whole organism level, I find that really amazing and intriguing."
The study, "Trans-vaccenic acid reprograms CD8+ T Cells and Antitumor Immunity," was supported by the National Institutes of Health (grants CA140515, CA174786, CA276568, 1375 HG006827, K99ES034084), a UChicago Biological Sciences Division Pilot Project Award, the Ludwig Center at UChicago, the Sigal Fellowship in Immuno- oncology, the Margaret E. Early Medical Research Trust, the AASLD Foundation, a Harborview Foundation Gift Fund, and the Howard Hughes Medical Institute.
