A person’s gut bacteria determine whether cancer treatment works

Diet and lifestyle 1. dec 2020 4 min Group Leader Zoltan Szallasi, Professor Laurence Zitvogel Written by Kristian Sjøgren

New research shows that people with lung cancer must have a very specific type of gut bacteria to enable immunotherapy to work properly.

Your gut is filled with billions and billions of bacteria, and these have a far greater effect on your health than you might imagine.

Gut bacteria can affect your risk of developing diseases such as Alzheimer’s or type 2 diabetes, and recent research has shown that gut bacteria also influence whether cancer treatment works.

A new study now shows why people with lung cancer need specific types of bacteria in the gut to optimize immunotherapy.

The research has been published in Science.

“A few years ago, our colleagues in France showed that antibiotic treatment before immunotherapy reduces its effectiveness because antibiotics kill a type of gut bacteria that is required for immunotherapy to be effective. In this study, we identified the mechanism behind the need for this type of bacteria,” explains a contributor to the study from Denmark, Zoltan Szallasi, Group Leader, Translational Cancer Genomics, Danish Cancer Society, Copenhagen.

Antibiotics inhibit the body’s immune response to cancer

The previous study from France showed that antibiotics kill Enterococcus hirae bacteria. This is a major problem because this type appears to be necessary for a good immune response with immunotherapy or chemotherapy.

The previous study showed that the immune response helps the body to identify and kill cancer cells, but without the bacteria, the immune system has trouble honing in on the right target and cannot destroy the cancer.

In the new study, the researchers showed how Enterococcus hirae helps the immune system hit the right target.

“Our previous study showed that Enterococcus hirae is capable of activating the immune killer cells called TMP1-specific cytotoxic T lymphocytes. They can identify cancer cells as being foreign and then kill them, thereby enabling the immune system to eliminate the cancer cells,” says another researcher behind the study, professor Laurence Zitvogel, Immunology and Immunotherapy Laboratory, Gustave Roussy Cancer Campus, Villejuif, France.

Bacteria express antigens similar to those cancer cells express

Cytotoxic T lymphocytes do not recognize the whole cancer cell but only a small antigen called a peptide on the surface of the cancer cell that acts as a signal for the killer cells.

However, if the cytotoxic T lymphocytes have encountered the antigen before, this is a huge advantage in getting them to recognize this signal as a target. This must be stored in the immune system’s memory, and this is the process underlying vaccine development. The vaccine teaches the killer cells to recognize antigens on the surface of viruses or bacteria so that they can immediately attack them if they encounter them.

This is where the new study comes in.

“We discovered that Enterococcus hirae expresses an antigen that is very similar to those expressed on the surface of cancer cells. This means that cytotoxic T lymphocytes that have previously encountered this bacterium can already identify cancer cells with similar surface antigens,” says Laurence Zitvogel.

The researchers also found that a family of bacteriophages (viruses that infect bacteria) called Siphoviridae also expresses the same antigen and can infect other bacteria and thus cause them to also express the antigen on the surface.

Further discoveries strengthen the evidence

To confirm their findings, the researchers examined how chemotherapy and immunotherapy affected mice with cancer that had an altered amino acid sequence for this antigen in either the bacteria or on the surface of the tumour cells.

This experiment showed that altering the antigen in either the tumour cells or in the bacteria caused the mice to lose the immune response, and the chemotherapy and immunotherapy lost the part of the healing effect that the immune system otherwise had.

Further, the researchers found that Enterococcus hirae, which does not carry the antigen on the surface, does not help the immune system to recognize tumour cells.

The researchers also performed experiments in which they exposed cytotoxic T lymphocytes to the antigens in cell culture and then determined whether they could recognize and kill tumour cells. The cytotoxic T lymphocytes could not do this once they had been exposed to altered antigens.

“The tumour cells carry an antigen that activates the killer cells, and we identified the peptide that does this,” says Zoltan Szallasi.

Researchers from Denmark sequenced the genome of gut bacteria

Zoltan Szallasi contributed to the study by sequencing the genome of the bacteria in stool samples from people with cancer.

Since thousands of bacterial species live in the gut, researchers cannot examine a sample under a microscope and identify whether, for example, Enterococcus hirae is present in the gut of a specific person.

Instead, the researchers analyse the total DNA in a person’s gut and then filter out all the DNA derived from the host and perform bioinformatic analysis on the remaining genomic data to identify the bacteria present based on the total genetic information.

The researchers can thereby determine whether Enterococcus hirae is present in the person’s gut.

“We can do this with each person with cancer to try and determine how well they will respond to immunotherapy,” explains Zoltan Szallasi.

Gut bacteria may be a target for new cancer treatments

Both Laurence Zitvogel and Zoltan Szallasi think that the new discovery has far-reaching perspectives.

Researchers can now explain why immunotherapy may be considerably less effective among people treated with antibiotics.

“For example, people with lung cancer often experience severe lung infections, and antibiotics kill the bacteria in their lungs but also those in their gut. This can mean that the subsequent immunotherapy does not work as well as it could otherwise,” says Zoltan Szallasi.

Laurence Zitvogel thinks that this discovery is only the first of several that will identify how the composition of gut bacteria influences the effectiveness of many treatments not only for cancer but also for other diseases.

“Considering the number of bacteria and bacteriophages in the gut, we think that various antigens must be present in the gut microbiome with many similarities to the antigens on the surface of diseased cells. These antigens can be used directly to stimulate the immune system and improve the effectiveness of cancer treatments. In the future, the microbiome may become a biomarker or even a target for new cancer treatments,” says Laurence Zitvogel.

Cross-reactivity between tumor MHC class I–restricted antigens and an enterococcal bacteriophage” has been published in Science. The Novo Nordisk Foundation awarded grants under its Interdisciplinary Synergy Programme to two co-authors, Zoltan Szallasi and Istvan Csabai.

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