The scientists of University of Chicago discovered that the trans-vaccenic acid (TVA), a fatty acid found in beef, lamb and dairy products, improves the ability of immune cells to fight tumors.
Transvaccenic acid (TVA), a long-chain fatty acid found in meat and dairy products from pastured animals like cows and sheep, enhances the ability of CD8+ T cells to infiltrate tumors and kill cancer cells, according to a new study led by researchers at the University of Chicago.
The research, published November 22 in the journal Naturealso shows that patients with higher levels of VAT circulating in the blood responded better to immunotherapy, suggesting that it may have potential as a nutritional supplement to complement clinical cancer treatments.
“Many studies attempt to decipher the connection 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 foods, we begin to see how they influence physiology and pathology,” said Jing Chen, PhD, the Janet Davison Rowley Distinguished Professor of Medicine at UChicago and one of the lead authors of the new study. “By focusing on nutrients that can activate T cell responses, we found one that actually boosts anti-tumor 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-first authors, assembled a “blood nutrient” compound library consisting of 255 nutrient-derived bioactive molecules. They screened compounds from this new library to determine their ability to influence anti-tumor immunity by activating CD8+ T cells, a group of immune cells essential for the destruction of cancer or virus-infected cells.
After the scientists evaluated the top six candidates in human and mouse cells, they found that TVA performed best. TVA is the most abundant trans fatty acid found in breast milk, but the body cannot produce it itself. Only about 20% of VAT is broken down into other byproducts, leaving 80% circulating in the blood. “That means there must be something else to do, so we started working on it more,” Chen said.
“To see that a single nutrient like TVA has a very targeted mechanism on a targeted immune cell type…I find that really amazing and intriguing.” »
— Jing Chen, PhD
The researchers then conducted a series of experiments with cells and mouse models of various tumor types. 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 the ability of CD8+ T cells to infiltrate tumors.
The team also carried out a series of molecular and genetic analyzes to understand how VAT affected T cells. This included a new technique for monitoring the transcription of single-stranded signals. DNA called kethoxal-assisted single-stranded DNA sequencing, or KAS-seq, developed by Chuan He, PhD, the John T. Wilson Distinguished Professor of Chemistry at UChicago and another senior author of the study. These additional analyses, performed by the Chen and He labs, showed that TVA inactivates a cell surface receptor called GPR43, which is typically activated by short-chain fatty acids often produced by the gut microbiota. TVA harnesses these short-chain fatty acids and activates a cell signaling process known as the CREB pathway, which is involved in various functions including cell growth, survival and differentiation. The team also showed that mouse models in which the GPR43 receptor was exclusively removed from CD8+ 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 collected from patients undergoing CAR-T cell immunotherapy treatment for lymphoma. They found that patients with higher levels of VAT tended to respond better to treatment than those with lower levels. They also tested leukemia cell lines working with Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine, and found that TVA improved an immunotherapy drug’s ability to kill leukemia cells.
Beyond Diet: Focusing on Nutritional Supplements
The study suggests that TVA could be used as a dietary supplement to aid various T-cell-based cancer treatments, although Chen emphasizes that it is important to determine the optimized amount of the nutrient itself, not the source eating. There is growing evidence on the adverse health effects of excessive consumption of red meat and dairy products. So this study shouldn’t be seen as an excuse to eat more cheeseburgers and pizza; Rather, it indicates that nutrient supplements such as TVA could be used to promote T cell activity. Chen thinks there may be other nutrients that can do the same.
“There is preliminary data showing that other fatty acids from plants signal through a similar receptor, so we think there is a strong possibility that nutrients from plants can also do the same thing by activating the CREB pathway” , did he declare.
The new research also highlights the promise of this “metabolomics” approach to understanding how the building blocks of food affect 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 like aging.
“After millions of years of evolution, only a few hundred food-derived metabolites end up circulating in the blood, meaning they might have some importance in our biology,” Chen said. “To see that a single nutrient like TVA has a very targeted mechanism on a targeted type of immune cell, with a very profound physiological response at the level of the whole organism, I find that really astonishing and intriguing. »
Reference: “Trans-vaccine acid reprograms CD8+ T cells and anti-tumor immunity” by Hao Fan, Siyuan Xia, Junhong Xiang, Yuancheng Li, Matthew O. Ross, Seon Ah Lim, Fan Yang, Jiayi Tu, Lishi Xie, Urszula Dougherty, Freya Q. Zhang, Zhong Zheng, Rukang Zhang, Rong Wu, Lei Dong, Rui Su, Xiufen Chen, Thomas Althaus, Peter A. Riedell, Patrick B. Jonker, Alexander Muir, Gregory B. Lesinski, Sarwish Rafiq, Madhav V. Dhodapkar, Wendy Stock, Olatoyosi Odenike, Anand A. Patel, Joseph Opferman, Takemasa Tsuji, Junko Matsuzaki, Hardik Shah, Brandon Faubert, Shannon E. Elf, Brian Layden, B. Marc Bissonnette, Yu-Ying He, Justin Kline, Hui Mao, Kunle Odunsi, Xue Gao, Hongbo Chi, Chuan He and Jing Chen, November 22, 2023, Nature.
The study 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 Ludwig Center at UChicago, the Sigal Fellowship in Immuno-Oncology, the Margaret E. Early Medical Research Trust, the AASLD Foundation and Harborview Foundation Gift Fund and Howard Hughes Medical Institute.