According to a recent study from the University of Chicago, trans-vaccenic acid (TVA), a long-chain fatty acid found in meat and dairy products from grazing animals such as cows and sheep, enhances the capacity of CD8+ T lymphocytes to infiltrate tumors and destroy cancer cells.
The study, published this week in Nature, also found that individuals with greater amounts of TVA in their blood reacted better to immunotherapy, suggesting that it may be used as a nutritional supplement to support clinical cancer therapies.
“There are many studies attempting to decipher the link between diet and human health, and understanding the underlying mechanisms is extremely difficult due to the wide variety of foods people eat.” “However, if we focus solely on nutrients and metabolites derived from food, we can 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 study’s senior authors. “By focusing on nutrients that can activate T cell responses, we found one that actually enhances anti-tumor immunity by activating an important immune pathway.”
Identifying foods that stimulate immune cells
Chen’s group studies how metabolites, minerals, and other chemicals in the blood impact cancer growth and response to cancer therapies. For the current work, two postdoctoral colleagues, Hao Fan, PhD, and Siyuan Xia, PhD, both co-first authors, began with a database of about 700 known food metabolites and constructed a “blood nutrient” compound library comprising 235 bioactive compounds generated from nutrients. They looked for chemicals in this novel library that may impact anti-tumor immunity by activating CD8+ T cells, a kind of immune cell that is essential for destroying malignant or virally infected cells.
TVA outperformed the other five choices in both human and mouse cells, according to the research. TVA is the most prevalent trans fatty acid found in human milk, yet it cannot be produced by the body on its own. Only around 20% of TVA is converted into various metabolites, leaving the remaining 80% circulating in the circulation. “That means there must be something else it does, so we started working on it more,” Chen went on to say.
Following that, the researchers performed a series of studies using cells and mice models of several tumor kinds. When mice were provided a TVA-enriched diet, the tumor growth capacity of melanoma and colon cancer cells was considerably decreased compared to animals fed a control diet. The TVA diet also improved CD8+ T cell infiltration into malignancies.
The researchers also conducted molecular and genetic tests to determine how TVA affected T cells. Chuan He, PhD, the John T. Wilson Distinguished Service Professor of Chemistry at UChicago and another senior author of the paper, created a novel approach for monitoring transcription of single-stranded DNA called kethoxal-assisted single-stranded DNA sequencing, or KAS-seq. TVA inactivates a cell surface receptor called GPR43, which is normally triggered by short-chain fatty acids generated by gut bacteria, according to these new studies performed by both the Chen and He laboratories. TVA overwhelms these short-chain fatty acids and activates the CREB pathway, which is involved in a range of tasks such as cellular growth, survival, and differentiation. The researchers also demonstrated that mice models in which the GPR43 receptor was only found on CD8+ T cells lacked the increased tumor-fighting capabilities.
Finally, the researchers collaborated with Justin Kline, MD, Professor of Medicine at UChicago, to study blood samples from lymphoma patients receiving CAR-T cell immunotherapy. They discovered that patients with greater levels of TVA responded better to therapy than those with lower levels. Working with Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine, they also investigated leukemia cell lines and discovered that TVA improved the capacity of an immunotherapy medicine to destroy leukemia cells.
Concentrate on the nutrition rather than the meal.
The findings implies that TVA might be utilized as a dietary supplement to aid in different T cell-based cancer therapies, while Chen emphasizes that the optimal dosage of the vitamin itself, not the food source, must be determined. There is a growing body of research regarding the negative health implications of eating too much red meat and dairy, so this study shouldn’t be used to justify eating more cheeseburgers and pizza; rather, it suggests that nutritional supplements like TVA might be used to enhance T cell activation. Chen believes that additional nutrients may have the same effect.
“There is early data showing that other fatty acids from plants signal through a similar receptor, so we believe there is a high possibility that nutrients from plants can do the same thing by activating the CREB pathway as well,” he said.
The new study also emphasizes the potential of this “metabolomic” approach to understanding how the components of our food impact our health. Chen and his colleagues seek to create a complete library of nutrients flowing in the blood in order to better understand their effects on immunity and other biological processes such as aging.
“After millions of years of evolution, there are only a couple hundred metabolites derived from food that end up circulating in the blood, so that means they could have some importance in our biology,” says Chen. “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 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 funded the study.
