[Nov. 29, 2023: JD Shavit, The Brighter Side of News]
A long-chain fatty acid commonly found in meat and dairy products from grazing animals, can significantly enhance the effectiveness of CD8+ T cells in infiltrating tumors and eradicating cancerous cells. (CREDIT: Creative Commons)
In a groundbreaking study published this week in the prestigious journal Nature, researchers from the University of Chicago have revealed a remarkable discovery: trans-vaccenic acid (TVA), a long-chain fatty acid commonly found in meat and dairy products from grazing animals, can significantly enhance the effectiveness of CD8+ T cells in infiltrating tumors and eradicating cancerous cells.
This breakthrough has far-reaching implications for the future of cancer treatment, suggesting that TVA could be harnessed as a potential nutritional supplement to augment existing clinical therapies.
Dr. Jing Chen, the Janet Davison Rowley Distinguished Service Professor of Medicine at the University of Chicago and one of the senior authors of the study, emphasized the importance of this research, stating, "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."
TVA's role in enhancing anti-tumor immunity emerged from a comprehensive investigation conducted by Dr. Chen's laboratory.
Postdoctoral fellows Dr. Hao Fan and Dr. Siyuan Xia, co-first authors of the study, created a "blood nutrient" compound library comprised of 255 bioactive molecules derived from nutrients. They meticulously screened these compounds to identify those capable of activating CD8+ T cells, a crucial component of the immune system responsible for targeting and destroying cancerous or virally infected cells.
Among the candidates tested, TVA emerged as the most potent activator of CD8+ T cells. This fatty acid, abundant in human milk but not produced by the body itself, captured the researchers' attention due to its unique properties. Approximately 80% of TVA remains in the bloodstream, indicating its potential significance in other physiological processes.
To unravel TVA's impact on anti-tumor immunity, the research team conducted a series of experiments using cell cultures and mouse models representing diverse tumor types. Mice fed a diet enriched with TVA exhibited substantially reduced tumor growth in melanoma and colon cancer models compared to those on a control diet. Moreover, the presence of TVA boosted the ability of CD8+ T cells to infiltrate tumors, a pivotal step in cancer eradication.
Research by Jing Chen, Chuan He, and team suggests that TVA could have potential as a nutritional supplement to complement clinical treatments for cancer. (CREDIT: NIH)
To gain insight into the molecular mechanisms underlying TVA's effects on T cells, the researchers employed advanced techniques, including kethoxal-assisted single-stranded DNA sequencing (KAS-seq), developed by Dr. Chuan He, the John T. Wilson Distinguished Service Professor of Chemistry at UChicago. These analyses revealed that TVA deactivates the GPR43 receptor on the cell surface, typically activated by short-chain fatty acids produced by gut microbiota.
By overpowering these short-chain fatty acids, TVA initiates the CREB pathway, a cellular signaling process critical for functions such as growth, survival, and differentiation. Remarkably, mice models with the exclusive removal of the GPR43 receptor from CD8+ T cells showed diminished tumor-fighting capabilities, underscoring the central role of this receptor in TVA's immune-boosting effects.
Human or mouse primary CD8+ T cells were isolated, activated and treated with or without TVA for different durations, followed by integrated, temporal mechanistic studies. (CREDIT: Nature)
In collaboration with Dr. Justin Kline, Professor of Medicine at UChicago, the research team analyzed blood samples from patients undergoing CAR-T cell immunotherapy for lymphoma. Their findings indicated that individuals with higher levels of TVA in their blood exhibited more favorable responses to treatment. Additionally, cell lines from leukemia showed that TVA enhanced the efficacy of an immunotherapy drug against cancerous cells, further supporting TVA's potential as an adjunct to cancer treatments.
However, it is crucial to note that the study's implications do not endorse a diet rich in red meat and dairy, which are associated with adverse health effects when consumed excessively. Dr. Chen emphasizes the need to focus on nutrients rather than the food source itself. He suggests that TVA could be administered as a dietary supplement to enhance T cell activity, and there may be other nutrients with similar effects. "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," Dr. Chen stated.
Principal component analysis of genes from RNA-seq analysis of siRNA-mediated transient knockdown of Creb1 (siCreb1) in CD8+ T cells with or without TVA treatment, compared to non-targeting control siRNA (siNTC) (n = 3). (CREDIT: Nature)
This groundbreaking research underscores the potential of a "metabolomic" approach to comprehending how dietary components impact our health. Dr. Chen and his team aspire to establish an exhaustive library of nutrients circulating in the blood, shedding light on their influence on immunity and various biological processes, including aging.
"After millions of years of evolution, there are only a couple of hundred metabolites derived from food that end up circulating in the blood, so that means they could have some importance in our biology," Dr. Chen remarked. "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."
While the research is in its early stages, it represents a significant step forward in understanding the intricate interplay between diet, nutrients, and the immune system. As scientists continue to unravel the mysteries of our metabolic pathways, we may unlock new strategies to bolster our body's defenses against cancer and other diseases.
For more science news stories check out our New Innovations section at The Brighter Side of News.
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