The microbiome is believed to play a role in the development of chronic inflammatory bowel diseases, trigger diabetes, produce obesity, and even cause neurological diseases like multiple sclerosis and Parkinson’s disease, not to mention depression and autistic disorders. The microbiome refers to the large assortment of bacteria found in the human gut. Each person’s digestive tract is believed to have over 100 trillion bacterial cells from several thousand different species.
For the past 20 years, the microbiome has been the focus of research, especially since a new technique called high-throughput sequencing made it feasible to analyze bacteria fast and precisely. Since then, there has been a growing amount of evidence indicating the microbiome, often known as the second human genome, is important for not only digestion but also regulates, if not controls, a wide range of physiological functions, the immune system especially.
For the first time, researchers from the Universities of Würzburg and Marburg have successfully demonstrated that bacterial metabolites can improve the cytotoxic activity of particular immune cells, thereby improving the efficacy of tumor therapy. In an ideal world, the microbiome’s bacterial species composition may be used to modulate the microbiome’s impact on the therapy’s efficacy.
The findings of the study were published in the journal Nature Communications. The discovery was made by Dr. Maik Luu, a postdoc in Professor Michael Hudecek’s laboratory at the Medical Clinic and Polyclinic II at the University Hospital of Würzburg. Professor Alexander Visekruna of the Philipps University in Marburg’s Institute of Medical Microbiology and Hygiene, where Luu undertook research before transferring to Würzburg, was another participant.
“We were able to show that the short-chain fatty acids butyrate and, in particular, pentanoate are increase the cytotoxic activity of CD8 T cells,” Maik Luu says of the study’s main finding. Killer cells are another name for CD8 T cells. It is their job as part of the immune system to kill cells that are damaging to the organism.
Short-chain fatty acids, on the other hand, are the gut microbiome’s most common metabolite class. On the one hand, they can increase T cell metabolism by activating central energy metabolism regulators. They can, on the other hand, hinder certain enzymes that control access to genetic material and, as a result, gene expression in T cells. They accomplish so by inducing epigenetic changes.
“When short-chain fatty acids reprogram CD8 T cells, one of the results is increased production of pro-inflammatory and cytotoxic molecules,” Luu describes. Treatment with the fatty acid pentanoate improved the ability of tumor-specific T lymphocytes to combat solid tumor models in the experiment. The scientist explains, ” We were able to observe the same effect when fighting tumor cells with so-called CAR-T cells.”
“Chimeric antigen receptor T cells” is how CAR-T cells are written. Normal T cells are essentially “blind” to tumor cells, but CAR T cells, thanks to a genetic change, are able to recognize particular target antigens on the tumor surface and kill cancer cells. Michael Hudecek is one of the foremost authorities on CAR-T cell research.
“The results are an example of how metabolites of intestinal bacteria can change the metabolism and gene regulation of our cells and thus positively influence the efficiency of tumor therapies,” Luu explains. This could improve the use of CAR-T cells against solid malignancies in particular.
In many circumstances, genetically engineered cell therapy has proven to be significantly less effective than treatment for haematological tumors like leukemia. The scientists believe that this could alter if the CAR-T cells were treated with pentanoate or other short-chain fatty acids before being employed in patients.
This impact could be precisely exploited by altering the makeup of the bacterial intestine colonisation, especially since Luu and his colleagues were able to identify the intestinal flora’s important pentanoate producer, Megasphaera massiliensis.
However, there is still a long way to go before the new discoveries lead to novel cancer medicines. In a further stage, the study team will broaden the scope of tumor disorders studied, including, in addition to other solid tumors, haematological tumor diseases such multiple myeloma. It also aims to dig deeper into the role of short-chain fatty acids in order to pinpoint potential targets for targeted genetic changes.
The study was published on July 1st, 2021 in Nature Communications.
Abstract. Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.
Discussion. Our study illustrates one potential embodiment to exploit the beneficial effect of pentanoate and butyrate on CTL function, i.e. SCFA-treatment during CTL manufacturing, which can readily be implemented in clinical-grade GMP manufacturing processes44. Another potential embodiment is the administration of pentanoate, butyrate or other SCFAs, or the transfer of a bacterial consortium that produces these SCFAs to patients that have received adoptive cell therapy. However, the clinical implementation of this embodiment will require careful additional investigations to determine the optimal route, dosing, and schedule in order to balance the stimulation of effector vs. regulatory immune cell subsets in favor of the desired therapeutic outcome.
Luu, M., Riester, Z., Baldrich, A. et al. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat Commun 12, 4077 (2021). https://doi.org/10.1038/s41467-021-24331-1