A team Inserm Lille, in collaboration with other Inserm laboratories, has just detailed the cascade of events which explains how certain bacteria in the microbiota, once infiltrated within a colorectal tumor, limit the action of chemotherapy.
Some colorectal cancers, particularly those affecting the right segment of the colon, do not always respond properly to conventional chemotherapies such as oxaliplatin. The analysis of the microenvironment of tumors, from patients followed at the Henri-Mondor University Hospital in Créteil and at the Clermont-Ferrand University Hospital, allowed Lille researchers to identify a strong presence of bacteria from the family of Escherichia coli. However, it has also been described that some of these bacteria produce an intestinal toxin – colibactin – which is both genotoxic (i.e. responsible for damage to the DNA of their host’s cells) and protumoral. The researchers were able to confirm that the prognosis of the tumors analyzed depends on the intratumoral presence ofEscherichia coli colibactin producers (or CoPEc for Colibactin producing Escherichia coli). They then sought to understand the mechanisms that link the presence of these bacteria and the evolution of the disease. This work led them to highlight changes in the metabolism and behavior of infected cancer cells, which become less visible to the patient’s anti-tumor immunity and less sensitive to the action of chemotherapy.
The originality of this work was to focus on the geolocation of bacteria, metabolites and immune cells within the microenvironment. An approach which was able to be carried out thanks to the financial support of the Tumor Heterogeneity program of the Cancer plan, BPIfrance, the i‑SITE foundation and the START-AIRR program of the Hauts-de-France region. Tumors with poor prognosis were more massively infiltrated by CoPEc than others. “ But the distribution of these bacteria is not homogeneous within cancerous tissue. », Explains Mathias Chamaillard, who directed the work of Nilmara de Oliveira Alves Brito, an Inserm researcher in his laboratory. “ Also, we analyzed the metabolic and immune activity in the vicinity of the bacteria. It appeared that the tumor cells which are in contact with them do not have the same immunometabolic profile as those which are further away: they are much richer in glycerophospholipid droplets, compounds known to be immunosuppressive. »
The effectiveness of chemotherapy also relies on immunity
But how could molecules that reduce the activity of anti-tumor immunity promote resistance to chemotherapy? “ Often the activity of chemotherapy is reduced to its action cytotoxicrecognizes the researcher. But its effectiveness is also mediated by our defense mechanisms: by killing cancer cells, chemotherapy causes the formation of cellular debris which is spotted by T lymphocytes. CD8. These immune cells then recruit other effectors to infiltrate the tumor together and reach tumor cells that have not necessarily been in contact with chemotherapy. This is the concept of cell death immunogenic. » The analyzes by the Lille team also show that tissue areas rich in glycerophospholipids are less infiltrated by these lymphocytes than areas where these bacteria were not present.
Other work supports these results: those carried out with Iradj Sobhani from CHU Henri-Mondor showed that blocking the synthesis of lipids by tumor cells limits their chemoresistance. Those led by Richard Bonnet in the Clermont unit Microbes intestinal inflammation and host susceptibility confirm that tumor cells become less differentiated and thus more chemoresistant after infection by CoPEc. “ Our results clarify how colibactin may promote chemoresistance. This paves the way for the development of new therapies to target the steps that allow lipid droplet accumulation and cell dedifferentiation. »
Mathias Chamaillard is Inserm research director, head of the Inflammasome and ion channels team and deputy director of the Cellular Physiology laboratory: ion channels, inflammation and cancer (unit 1003 Inserm/University of Lille), at ONCOLIlle.
Richard Bonnet is a researcher in the Microbes, gut, inflammation and host susceptibility unit (unit 1071 Inserm/Clermont Auvergne University) in Clermont-Ferrand
Source : N. de Oliveira Alves et al. The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance. Gut Microbes, February 28, 2024; doi:10.1080/19490976.2024.2320291
Author: C.G.
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