A team of investigators at the Universities of Würzburg and Marburg have succeeded, for the first time, in experimentally demonstrating that bacterial metabolites can increase the cytotoxic activity of specific immune cells and thus positively influence the efficiency of tumor therapies. Findings from the new study were published recently in Nature Communications through an article entitled “Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer.” The researchers are optimistic that the composition of the bacterial species of the intestinal microbiome could be used to control its influence on the success of cancer therapy.
“We were able to show that the short-chain fatty acids butyrate and, in particular, pentanoate can increase the cytotoxic activity of CD8 T cells,” explained lead study investigator Maik Luu, PhD, a postdoctoral researcher at the Medical Clinic and Polyclinic II of the University Hospital of Würzburg. “CD8 T cells are sometimes also called killer cells. As part of the immune system, it is their task to kill cells that are harmful to the organism specifically.”
For some time now, scientists have believed that the gut microbiome is involved in the development of chronic inflammatory intestinal diseases, to trigger diabetes, to be responsible for obesity, even neurological conditions such as multiple sclerosis and Parkinson’s could have their causes here—not to mention depressions and autistic disorders. It is estimated that each person carries around 100 trillion bacterial cells in their digestive tract, belonging to several thousand species.
The microbiome has been the focus of research for 20 years—ever since a new technique made it possible to analyze these bacteria quickly and precisely: high-throughput genomic sequencing. Since then, there has been an increasing body of findings that the microbiome, which is sometimes also referred to as the second human genome, is not only of central importance for digestion but also influences, if not controls, at least a large number of body functions. The immune system is mentioned particularly frequently.
Short-chain fatty acids belong to the most dominant class of metabolites of the gut microbiome. On the one hand, they can boost the metabolism of T cells by inducing central regulators of energy metabolism. But, on the other hand, they can inhibit specific enzymes that regulate the accessibility to the genetic material and thus the gene expression in the T cells. In doing so, they induce 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 noted. In the experiment, treatment with the fatty acid pentanoate increased the ability of tumor-specific T cells to fight solid tumor models. “We were able to observe the same effect when fighting tumor cells with so-called CAR-T cells.”
While normal T cells are largely “blind” to tumor cells, CAR T cells can recognize specific target antigens on the tumor surface and destroy the cancer cells thanks to a genetic modification.
“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 stated. In particular, the use of CAR-T cells against solid tumors could benefit from this.
In these cases, therapy with genetically modified cells has so far been much less effective than the treatment of hematological tumors such as leukemia. However, this could change if the CAR-T cells were treated with pentanoate or other short-chain fatty acids before being used in patients, the scientists hope.
This effect might specifically be exploited via the composition of the bacterial intestinal colonization—especially since Luu and the others involved in the study were also able to identify the essential pentanoate producer of the intestinal flora: the bacterium Megasphaera massiliensis.
However, there is still a long way to go before the new findings will lead to new therapies for cancer patients. In the next step, the research team will initially expand the spectrum of tumor diseases investigated and, in addition to other solid tumors, also look at hematological tumor diseases such as multiple myeloma. In addition, it wants to investigate the functioning of short-chain fatty acids more intensively to identify starting points for targeted genetic modifications.
