In recent years, the intestinal flora has been a research hotspot. More and more findings indicate that the intestinal flora is not only central importance to digestion, but also affects a wide range of bodily functions. They are thought to be related to chronic inflammatory bowel disease, diabetes, obesity, Parkinson's disease, and even depression and autism.
Recent studies have shown that the intestinal flora can directly affect the effect of cancer immunotherapy. However, there is very little research on the role of intestinal flora metabolites in regulating cancer immunotherapy. Acetate, propionate and butyrate are the main microbial metabolites and belong to the short-chain fatty acid (SCFA) category. They can promote the expansion of Treg cells and improve the function of effector T cells.
On July 1, 2021, the research team from the Philipps University of Marburg, Germany published a research paper titled: Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer in Nature Communications.
This study is the first experiment to prove that the two microbial metabolites, valeric acid and butyric acid, enhance the anti-tumor activity of immune cells through metabolism and epigenetic reprogramming, confirming that valeric acid and butyric acid have optimal effects in cancer immunotherapy.
Symbiotic bacteria containing broad-spectrum enzymes can produce a variety of small molecules that can be used for therapeutic intervention. The research team observed that the low-abundance human symbiotic bacterium M. massiliensis is the only bacterium that synthesizes large amounts of short-chain fatty acids (SCFA), valeric acid and butyric acid.
They then treated CD8 + T cells with supernatant containing valeric acid and butyric acid from M. massiliensis to observe their functional changes. The results showed that valeric acid and butyric acid produced by M. massiliensis enhanced the production of effector cytokines in CD8 + T cells.
Short-chain fatty acids (SCFA) are known inhibitors of histone deacetylase (HDAC) that can regulate the fate of eukaryotic cells through epigenetic methods.
The research team compared the histone deacetylase (HDAC) inhibitory activity of the supernatants from 16 species of human symbiotic bacteria. They found that butyrate and valerate inhibit HDAC class I enzymes, reprogram CD8 + T cells, and increase the production of pro-inflammatory and cytotoxic molecules.
Further experimental results show that treatment with fatty acid valerate enhances the ability of tumor-specific T cells against solid tumor models.
Normal T cells are largely "blind" to tumor cells, while CAR-T cells can recognize specific target antigens on the tumor surface and kill cancer cells. Therefore, in order to further develop potential treatment strategies, the research team studied the impact of short-chain fatty acids (SCFA) on CAR-T cell therapy.
They found that valerate treatment enhanced the therapeutic effect of CAR-T cell therapy on pancreatic cancer, demonstrating the potential of using valeric acid and butyric acid to optimize CAR-T cell generation to enhance the efficacy of CAR-T cells following adoptive metastasis.
In summary, the study revealed two microbial metabolites valeric acid and butyric acid that can be used to enhance cellular anti-tumor immunity, and demonstrated two potential anti-tumor therapies: one is the use of valeric acid and butyric acid to optimize cytotoxic T cells; the other one is to transfer the bacterial population that produces these short-chain fatty acids (SCFA) to patients receiving adoptive cell therapy.
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Reference:
https://www.nature.com/articles/s41467-021-24331-1