University of Chicago researchers have identified a nutrient derived from beef, lamb, and dairy products that could enhance cancer therapies.
Hao Fan and co-authors report in Nature that the long-chain fatty acid trans-vaccenic acid (TVA) promotes the tumor-infiltrating and cytotoxic functions of CD8+ T cells and “has high translational potential as a dietary element in therapeutic approaches to improve clinical outcomes of diverse anti-cancer therapies such as immune checkpoint inhibitors, T cell engagers and CAR-T and T cell receptor T cell therapy.”
The investigators identified TVA when they screened 235 blood nutrients for their ability to influence anti-tumor immunity by activating CD8+ T cells, which play a key role in killing cancerous cells.
“There are many studies trying to decipher the link between diet and human health, and it’s very difficult to understand the underlying mechanisms because of the wide variety of foods people eat. But if we focus on just the nutrients and metabolites derived from food, we begin to see how they influence physiology and pathology,” says Jing Chen, PhD, the Janet Davison Rowley Distinguished Service Professor of Medicine at the University of Chicago and one of the senior authors of the study. “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.”
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 says.
The researchers conducted a series of experiments in tumor cells and mouse models of diverse tumor types that confirmed that TVA promotes anti-tumor immunity through regulation of CD8+ T cells. They then showed that 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 enhanced the ability of CD8+ T cells to infiltrate tumors.
Next, the team performed a series of molecular and genetic analyses to understand the mechanism behind the effect that TVA has on the T cells. These additional assays showed for the first time that TVA inactivates a cell surface receptor called GPR43 which is usually activated by short-chain fatty acids often produced by 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 work “uncovers the importance of the previously undervalued CREB pathway in CD8+ T cell function,” Chen tells Inside Precision Medicine.
Finally, the team investigated whether TVA levels impact T cell based anti-cancer therapies. They analyzed blood samples taken from patients undergoing CAR-T cell immunotherapy treatment for lymphoma and found that TVA levels were higher in the patients who responded to the therapy than in non-responders. They also tested the effect of TVA on leukemia cell lines and observed that adding the nutrient enhanced the ability of the immunotherapy drug blinatumomab to kill the cells in vitro.
The study therefore suggests that TVA could be used as a dietary supplement to help various T cell-based cancer treatments. However, Fan and colleagues point out that although consuming red meat may provide TVA for improved anti-tumor immunity, a high intake of red meat has been positively associated with risk of many cancers, including breast, colorectal, colon and rectal cancer.
“Thus, our studies support TVA supplementation as a more targeted and efficient way than dietary changes to benefit anti-tumor immunity,” they write.
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, 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,” Chen says. “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.”
