2023-11-22 18:08:55
Meat and dairy products from grazing animals such as cows and sheep contain a long-chain fatty acid, called transvaccenic acid (TVA), which improves the capacity of CD8+ T cells of the immune system to infiltrate tumors and kill cancer cells, according to a new study from the University of Chicago.
The research, published this week in Nature, also shows that patients with higher levels of TVA circulating in the blood responded better to immunotherapysuggesting that it could 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,” says Dr. Jing Chen, Janet Davison Rowley Distinguished Service Professor of Medicine at the University of Chicago 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 improves anti-tumor immunity by activating an important immune pathway,» she adds.
Chen’s lab focuses on understanding how metabolites, nutrients and other molecules circulating in the blood influence cancer development and response to treatments. For the new study, two postdoctoral fellows, Hao Fan and Siyuan Xia, both co-authors, started with a database of around 700 known metabolites that come from food and assembled a ‘blood nutrient’ compound library consisting of 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 fundamental immune cells to kill cancerous 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 notes.
The researchers then carried out a series of experiments using cells and mouse models of various types of tumors. Feed the mice a TVA-enriched diet significantly reduced tumor growth potential of melanoma and colon cancer cells compared to mice fed a control diet. The TVA diet too improved the capacity of CD8+ 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, developed by Dr. Chuan He, Professor of Chemistry with John T. Wilson Distinguished Service at the University of Chicago and 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+ T cells also lacked its enhanced tumor-fighting ability.
Finally, the team also worked with Justin Kline, a professor of medicine at the University of Chicago, 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 professor of medicine Wendy Stock and saw that TVA improved the ability of a drug immunotherapy to kill leukemic cells.
The key is in the nutrients, not in the 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 of the detrimental health effects of consuming too much red meat, so this study should not be taken as an excuse to eat more, but rather indicates that nutritional supplements such as TVA could be used to promote the activity of T cells. Chen believes there may be other nutrients that can do the same.
“There is initial data showing that other plant fatty acids send signals through a similar receptor, so we believe there is a high possibility that plant nutrients can do the same by also activating the CREB pathway,” he clarifies. .
The new research also highlights the promise of this ‘metabolomic’ approach to understanding how the 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 of hundred food-derived metabolites that end up circulating in the blood, which means they could have some importance in our biology. “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,” says Chen.
For his part, Nabil Djouder, head of the Growth Factors, Nutrients and Cancer Group at the National Cancer Research Center (CNIO), in statements to SMC Spain, positively values this research and its results: «The conduct of this study is globally remarkable, since it has a careful implementation, a mechanism of action clarified with the identification of the receptor modulated by TVA in immune cells and tests carried out both in mice and in patient samples. These aspects convincingly suggest its potential translational application in cancer treatment. The research highlights the importance of individual nutrients by establishing links between diet and human physiology and pathology. Several studies, including those conducted by my group, have demonstrated the crucial role of diets and vitamins, such as vitamin B3in the prevention of cancer and other diseases.”
The expert also remembers that TVA is a natural chemical compound belonging to the group of unsaturated fatty acids. «It is found in the ruminant fatsin it fish oilin blood plasma and in microorganisms such as species of Lactobacilluswhich are important probiotic bacteria in the production of yogurt and milk fermentation,” he concludes.
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