A new study finds that trans-tallow acid, a fatty acid found in dairy products and meat from pasture-raised animals, may boost the cancer-fighting abilities of immune system T cells. The nutrient has also been found to enhance the effectiveness of immunotherapy and could potentially be used as a nutritional supplement to complement cancer treatments.
Diet has been shown to provide a range of health benefits, including preventing the spread of cancer or enhancing treatment of the disease. However, due to the diversity of foods and the complexity of dietary metabolism, little is known about how specific nutrients affect physiological and pathological processes in the human body.
University of Chicago researchers solved this dilemma by building a library of blood nutritional compounds and screening their contents to identify nutrients that influence cancer development and its response to treatment.
"There are many studies trying to decipher the connection between diet and human health, but it is difficult to understand the underlying mechanisms due to the wide variety of foods people eat," said Chen Jing, the study's corresponding author. "But if we just focus on the nutrients and metabolites extracted from food, we start to see how they affect physiology and pathology."
The researchers' library contained 255 bioactive nutrient-derived molecules, which they screened for their ability to affect anti-tumor activity by activating the immune system's effector CD8+ T cells. When a naive T cell encounters an antigen, it differentiates into effector T cells. Cytotoxic CD8+ T cells are responsible for killing cancer cells or cells infected by pathogens and are a type of effector T cell. Of their "top six," they considered trans-tallow acid (TVA) to be the top performer.
"By focusing on nutrients that activate T-cell responses, we discovered a nutrient that can actually enhance anti-tumor immunity by activating important immune pathways," Chen said.
TVA is a natural trans fatty acid, mainly derived from the meat fat of ruminants, cattle, sheep and other herbivorous animals, as well as dairy products such as milk and butter; the human body cannot produce it on its own. Fun fact: TVA’s name comes from the Latin word for cow, vacca. Only about 20% of TVA is broken down into other by-products, with the remaining 80% circulating in the blood. "That meant it must have other effects, so we started studying it more," Chen said.
By conducting experiments on cell and mouse models of different tumor types, the researchers found that feeding mice a TVA-rich diet significantly reduced the tumor growth potential of melanoma and colon cancer cells compared with mice fed a control diet. The TVA diet, but not the control diet, led to an increase in the number of CD8+ T cells in tumor-infiltrating lymphocytes (TILs), which recognize cancer cells as abnormal cells and penetrate the tumor's microenvironment to kill them. Dietary TVA reduces CD8+ T cell exhaustion in tumors and promotes cell function, including survival. TVA diet did not affect CD8+ T cell populations and function in tumor-free mice, suggesting that the effects of dietary TVA on T cells may be dependent on generating an immune response.
The researchers performed molecular and genetic analyzes to determine the effects of TVA on T cells, including a new technique for monitoring single-stranded DNA (ssDNA) transcription called ketoaldehyde-assisted single-stranded DNA sequencing (KAS-seq). The analysis showed that TVA inactivates the immune cell surface receptor GPR43, which is normally activated by short-chain fatty acids produced by the gut microbiota. TVA overrides short-chain fatty acids and activates the CREB pathway, a cell signaling pathway involved in multiple functions, including cell growth, survival and differentiation. The researchers also found that mouse models that removed the GPR43 receptor from CD8+ T cells lacked enhanced anti-tumor capabilities.
The final step in the study was to analyze blood samples from patients who received chimeric antigen receptor (CAR)-T cell lymphoma immunotherapy. CAR-T cell therapy uses genetically modified T cells to target and destroy cancer cells more effectively. The researchers found that patients with higher TVA levels tended to respond better to treatment than those with lower levels. They also tested leukemia cell lines and found that TVA enhanced the ability of blinatumomab, an immunotherapy drug that acts on T cells, to kill leukemia cells.
The findings suggest that TVA could be used as a dietary supplement to increase the effectiveness of T cell-based cancer treatments. However, researchers are quick to point out that it is the nutrient itself, not the food source, that is important and advise against consuming too much red meat and dairy products to increase TVA levels, which can be harmful to health.
The study highlights the importance of the emerging field of metabolomics - the large-scale study of cellular metabolites - for understanding how our diet affects our health.
"After millions of years of evolution, only a few hundred metabolites from food end up circulating in the blood, so that means they may have some importance in our biology," Chen said. "To see that a single nutrient like TVA has a very targeted mechanism for targeting immune cell types, producing a very profound physiological response at a whole organism level - I found that really surprising and interesting."
The research was published in the journal Nature.