Connection Between Antibiotic Use, Intestinal Flora, and Immunotherapy Response in Cancer Patients

2023-06-14 16:06:00

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– Scientists from the Gustave Roussy Cancer Campus in France and the Heidelberg University Hospital discovered a connection between antibiotic use, disturbed intestinal flora, the behavior of inhibitory immune cells and poor response to immunotherapy in cancer
– Molecular mechanisms described in the journal “Science”.
– Follow-up study on the clinical application of the new findings is being prepared at the Heidelberg University Hospital

If cancer patients have to be treated with antibiotics because of a concomitant disease, they respond less well to immunotherapy against the tumor. The mechanisms that play a role here have not yet been fully elucidated. An international team from the Gustave Roussy Cancer Campus in France and the Heidelberg University Hospital (UKHD) has now published new findings in the renowned journal “Science”: The researchers discovered that when the intestinal flora has been damaged, for example by antibiotics, a signaling protein (MAdCAM-1) is present in its Function is disturbed, which sends immune cells intended for the intestine into the intestinal tissue. These immune cells ensure the balance between tolerance and containment of the intestinal bacteria by the immune system. If they can no longer get into the intestinal mucosa due to the missing protein and remain in the bloodstream, they are destroyed by Attractants from the tissue around the tumor are attracted and inhibit the defense reaction of the immune system there. They thus reduce the effect of cancer immunotherapy. The results could in future contribute to improving the chances of success of immunotherapies in cancer patients by building up the intestinal flora.

It has long been known that a damaged intestinal flora, also known as the intestinal microbiome, can have an unfavorable effect on cancer therapies. In the work now published in Science, the researchers from Heidelberg and Villejuif found a link between the intestinal microbiome and the immune system: “After antibiotic therapy, immune cells migrate from the intestine into the tumor, which we marked using specific staining methods and observed their movement in the body . The task of these T cells is normally to prevent excessive defense reactions in the intestinal mucosa so that contact between the bacteria in the intestinal flora and the immune system does not permanently lead to unwanted inflammation,” explains one of the first authors, Dr. Conrad Rauber, Clinic for Gastroenterology , Infectious Diseases and Poisoning of the UKHD, which conducted research at the Gustave Roussy Cancer Campus in Villejuif/France.

If the intestinal flora is weakened, immune cells that suppress immune reactions migrate into the tumor

Experiments on mice with a disturbed intestinal microbiome after administration of antibiotics focused on two molecular mechanisms that promote the migration of T cells: On the one hand, the intestinal mucosa releases fewer messenger substances, so-called chemokines, which tell the immune system that bacteria have contacted them, and on the other hand the formation of the signaling protein “Mucosal cell adhesion molecule” (MAdCAM-1), which allows the T cells to cross over from the blood vessels into the intestinal mucosa.

In simplified terms, this results in the following picture: The intake of antibiotics seems to reduce the intestinal flora to such an extent that the inflammatory potential of the intestinal mucosa and thus the need for anti-inflammatory T cells decreases. Fewer corresponding attractants are released and fewer shuttle proteins are formed. While the T-cells now face closed doors, they are susceptible to signals from other sources of inflammation and become stranded in the tumor, where they reduce the effectiveness of cancer immunotherapies.

“Our results could provide a concrete approach to assess before the start of therapy whether the respective patient has an intestinal flora that is favorable for the success of cancer immunotherapy,” says Dr. Rauber In the long term, cancer patients with a disturbed intestinal microbiome could be treated with stool transplants from healthy donors, for example, in order to improve the initial conditions for immunotherapy. Under no circumstances should necessary antibiotic therapies be dispensed with.” A follow-up project that will bring this approach to clinical application is already in preparation: a clinical study is expected to start at the UKHD in which patients with liver cancer will receive a stool transplant before immunotherapy in order to improve the immune response to the tumor.

literature

Fidelle M, Rauber C, Alves Costa Silva C, et al. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers. Science. 2023;380(6649):eabo2296. doi:10.1126/science.abo2296

Rauber C. A Study on the Role of the Intestinal MAdCAM-1/alpha4beta7 Axis in Tumor Immunosurveillance During PD-1 Blockade. Thèses 2019.

More information on the internet

UKHD Department of Gastroenterology, Infectious Diseases and Poisoning

Gustave Roussy Cancer Campus

FLORA Study