What is already known
Gut microbes can sway a person’s response to cancer immunotherapy, a type of treatment that helps the immune system fight tumor cells. Studies have shown that antibiotics can compromise clinical outcomes when administered before cancer immunotherapy, likely as a result of an altered gut microbiota. However, it’s unclear how a disrupted microbial composition influences the tumor microenvironment.
What this research adds
Researchers examined mice with cancer that received broad-spectrum antibiotics. They found that the rodents had lower intestinal levels of a molecule called MAdCAM-1, which is involved in a process that directs specific immune cells to different body sites. Mice that received antibiotics also had increased levels of two bacterial species that have been observed in the stools of people who do not respond to cancer immunotherapy. The team also found that metabolites from these bacteria drove the downregulation of MAdCAM-1 — an effect that ultimately directed specific immunosuppressive cells to the tumor microenvironment, where their activity worked against immunotherapy.
Conclusions
The findings suggest that targeting the interactions between MAdCAM-1 and specific receptors on the surface of immune cells may help to improve immunotherapy outcomes
Gut microbes can sway a person’s response to cancer immunotherapy, a type of treatment that helps the immune system fight tumor cells. Now, a study done in mice shows that antibiotics may induce the development of immunotherapy resistance by altering the gut microbiota.
The study, published in Science, also identified a potential marker of intestinal dysbiosis and suggested new molecular targets to improve immunotherapy outcomes.
Researchers have known that antibiotics can compromise clinical outcomes when administered before cancer immunotherapy, likely as a result of an altered gut microbiota. However, it’s unclear how a disrupted microbial composition influences the tumor microenvironment.
To address this question, Marine Fidelle at the Gustave Roussy Cancer Campus in Villejuif, France, and her colleagues evaluated the interplay between antibiotics, the gut microbiota and a specific group of intestinal T cells with immunosuppressive function, which are known to be regulated by gut microbes.
Hindering immunotherapy
The researchers gave broad-spectrum antibiotics to mice with fibrosarcomas, a rare and aggressive cancer. Antibiotic treatment resulted in lower intestinal levels of a molecule called MAdCAM-1, which is involved in a process that directs specific immune cells to different body sites.
Mice that received antibiotics also had increased levels of two bacterial species belonging to the genus Enterocloster. These bacteria have been observed in abundance in the stools of people who do not respond to cancer immunotherapy.
The team also found that metabolites from these bacteria drove the downregulation of MAdCAM-1. MAdCAM-1 typically binds a class of receptors called α4β7 on the surface of regulatory T cells, which have immunosuppressive functions. Dampening the levels of MAdCAM-1 ultimately directed these immunosuppressive cells to the tumor microenvironment, where their activity worked against immunotherapy, the researchers found.
Dysbiosis marker
Finally, the team showed that transferring gut microbes from lung cancer patients to mice treated with antibiotics prevented MAdCAM-1 reduction and kept regulatory T cells localized to the gut. This ultimately reduced the development of immunotherapy resistance.
In people with kidney, bladder and lung cancer, low blood levels of MAdCAM-1 were a proxy of intestinal dysbiosis and could predict worse clinical outcomes following immunotherapy, the researchers found.
MAdCAM-1 may thus be a potential marker of intestinal dysbiosis, the authors say. The findings also suggest that targeting the interactions between MAdCAM-1 and α4β7 receptors could help to improve immunotherapy outcomes.
