Radiation therapy effectiveness influenced by gut fungi

Cedars-Sinai scientists have discovered that intestinal microorganisms help regulate anti-tumour immune responses to radiation treatments, and that fungi and bacteria have opposing effects on those responses.

Their research, conducted in laboratory mice and published in the journal Cancer Cell, builds on prior studies that focused on the role of intestinal bacteria in influencing immune responses to chemotherapy and immunotherapy.

Trillions of microorganisms live in normal human intestines. These so-called commensal microorganisms are ‘friendly’ bacteria and fungi that help process nutrients and play key roles in regulating the immune system in everything from infections to allergies. The research team found that reducing levels of commensal fungi in the intestines enhanced the anti-tumour immune response in the mice following radiation therapy. Conversely, they showed that depletion of commensal bacteria reduced the anti-tumour response.

“Scientists have long known that bacteria in the gut influence the immune system,” said lead author Dr Stephen L Shiao, Director of the Division of Radiation Biology. “We now believe that a yin-and-yang relationship exists between intestinal bacteria and fungi. If you deplete bacteria with antibiotic use, for example, it upsets the balance in the microbiome — the community of bacteria, fungi and potentially other microbes in the body. The effect is to create space for fungi to proliferate and dampen the anti-tumour immune response.”

The potential impact of this discovery is wide-reaching because nearly half of patients diagnosed with cancer — including brain, head and neck, lung, breast, gynaecologic and prostate cancer — undergo radiation therapy as part of their treatment regimen, Dr Shiao explained.

“In our mouse studies, the impact of intestinal bacteria and fungi on the anti-cancer immune response was the same in both breast cancer and melanoma — very different cancers,” Dr Shiao said. “We think that this indicates that gut bacteria and fungi influence anti-tumour immune responses in many, if not all, types of cancer.”

It may seem odd that bacteria and fungi in the gut could affect the response to radiation therapy directed at cancers in other organs. This connection is rooted in the relationship between the biology of cancer and the immune system.

Cancer forms when cells in the body grow and divide uncontrollably. Certain types of immune cells patrol the body to identify and destroy tumour cells. This immune response is shaped by the microbiome. Sensors on immune cells detect specific microbes that stimulate different responses. The researchers discovered that one such sensor, Dectin-1, detects a sugar found only on the surface of fungi that prompts a braking signal to shut down an immune response. In contrast, bacteria send signals that strengthen immune responses. By reducing the number of fungi in mouse intestines, the team were able to strengthen the immune system’s attack on the tumour following radiation.

Although the major experimental parts of the study were performed in mice, the team also examined the level of Dectin-1 in patients with breast tumours. They found that higher expression of Dectin-1 was associated with worse survival, suggesting that this sensor may play the same role in patients with cancer.

Looking forward, the researchers hope to characterise the diversity of gut microorganisms in cancer patients undergoing treatment to better understand the mechanisms by which gut microbiota, such as bacteria and fungi, influence cancer therapies. The goal is to find the best way to optimise both the bacterial and fungal microbiome to promote anti-tumour immune responses, Dr Shiao said.

“Radiation therapy has always been a major part of cancer treatment,” said Dr Dan Theodorescu, Director of the Cedars-Sinai Cancer enterprise. “Now more than ever, precision delivery of radiation and its combination with immunotherapy — including manipulating host factors as described in this paper — will make this therapy even more effective for our patients.”

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