Certain bacteria in the microbiota may interfere with chemotherapy

Colorectal cancer, one of the most common in France, with around 50,000 new cases reported every year, does not always respond well to traditional chemotherapy methods. This is especially true for cancers affecting the right segment of the colon.

A team of scientists from the National Institute for Health and Medical Research (Inserm) has just identified the mechanisms involved in this chemoresistance. His work was published in the journal Gut Microbes.

Presence of E. coli bacteria in colorectal tumors

By analyzing the microenvironment of colorectal tumors in patients treated at Créteil and Clermont-Ferrand hospitals, the researchers were able to detect a significant presence of Escherichia coli bacteria. Some of them produce an intestinal toxin called colibactin, which is both genotoxic (i.e. responsible for damaging the DNA of host cells) and pro-tumor. However, scientists note that the prognosis of the analyzed tumors depends specifically on the intratumoral presence of colibactin-producing bacteria E. coli (or CoPEc, their English abbreviation). Thus, the most dangerous tumors were much more infiltrated with CoPEc than others.

“But the distribution of these bacteria in cancer tissue is not uniform.”, explains researcher Mathias Chamaillard, who took part in the study. By analyzing metabolic and immune activity near bacteria, “It turned out that the tumor cells that come into contact with them do not have the same immunometabolic profile as those that are further away: they are much richer in droplets of glycerophospholipids, compounds that are known to have immunosuppressive effects,” that is, a decrease in the activity of the immune system.

Cancer cells that become chemoresistant

But how can molecules that suppress antitumor immune activity contribute to chemotherapy resistance? “Efficiency [de la chimiothérapie] mediated by our defense mechanisms: by killing cancer cells, chemotherapy causes the formation of cellular debris, which is detected by CD8 T cells. These immune cells then recruit other effectors to work together to infiltrate the tumor and reach tumor cells that have not necessarily been exposed to chemotherapy. This is the concept of immunogenic cell death.” Researchers have observed that tissues rich in glycerophospholipids are less infiltrated by these lymphocytes than others.

It is clear that cancer cells infected with CoPEc become less differentiated, therefore less visible to the patient’s antitumor immunity and, therefore, less sensitive to the effects of chemotherapy. “Our results clarify how colibactin may promote chemoresistance. scientists conclude. This paves the way for the development of new treatments that target the steps that allow lipid droplet accumulation and cell dedifferentiation.”