In recent years, researchers have discovered that bacteria in the gut are necessary for robust responses to chemotherapy and immunotherapy, but their effects on radiation therapy remained unknown. Now, research published in Cancer Cell on July 29 demonstrates that not only are gut bacteria vital to radiation’s ability to fight tumors, but fungi—less famous members of the gut microbiome—may act as additional key regulators of the antitumor immune response.
The paper “represents the first demonstration that intestinal fungi may affect anti-cancer radiotherapy,” writes Giorgio Trinchieri, a cancer and immunology researcher at the National Cancer Institute who was not involved with the work, in an email to The Scientist. “I consider this paper an important contribution to the field.”
Researchers know that gut bacteria and fungi affect immune system function, and recent studies have shown that they also play a role in cancer development. Since certain cancer therapies generate antitumor immune responses, it makes sense that gut bacteria alter these drugs’ effectiveness as well: In preclinical models and previous human studies, effective chemotherapy and immunotherapy required intact intestinal bacterial communities. When researchers eliminated bacteria with antibiotics in mice, the effectiveness of chemotherapy drugs and immunotherapy decreased significantly.
No one had studied the interaction between the microbiome and radiation therapy. So two researchers at Cedars-Sinai Medical Center in Los Angeles joined forces—Stephen Shiao, a radiation oncologist, immunologist, and cancer researcher, and David Underhill, a microbiome and inflammation researcher—to examine it in mice. “We saw, interestingly, that [the efficacy of radiation] was affected by bacteria, like chemotherapy or immunotherapy,” said Shiao.
The team also saw that when the mice received antibiotics, fungi grew in the bacteria’s stead. “That was our aha moment,” he says, adding that it led to a hypothesis that perhaps an overgrowth of fungus was one of the reasons why, when gut bacteria are eliminated, cancer treatment becomes less effective.
Fungi in the microbiome have recently been shown to regulate inflammatory responses. To learn more about their role during radiation treatment, Shiao and his team used a mouse model of breast cancer, letting tumors grow and then irradiating them. When tumor-bearing mice received antibiotics, tumors grew back more quickly following radiation compared with controls who hadn’t received antibiotics, with no reduction in tumor cell proliferation compared to controls who hadn’t received radiation and less tumor cell death. Quantitative PCR of microbial ribosomal DNA obtained from mice feces revealed that antibiotics depleted bacteria more than 2000-fold, while fungal counts increased over 2000-fold. Giving mice with mammary tumors or melanoma an antifungal drug increased the radiation’s ability to delay tumor growth and improved survival, seemingly by increasing levels of tumor cell death after radiation therapy. They also created fungus-free mice and showed that radiation therapy was much more effective in them than in regular mice.
To determine precisely how fungi reduce the effectiveness of radiation therapy, the researchers examined the immune cell composition of tumors from mice that received the different treatments. Compared with mice receiving radiation alone, mice receiving radiation plus antifungal treatment had an increase in cell-killing CD8+ T cells. In mice receiving antibiotics plus radiation, they saw an increase in tumor-associated macrophages that attack these tumor cell-killing T cells. (Killing the bacteria leads to an increase in fungi.). When the team removed either these T cells or macrophages from the mice, the antifungal lost its tumor-slowing and life-prolonging effects.
In their paper, the researchers write that this likely means that bacteria are important for generating activated T cells after radiation therapy, while fungi promote macrophages that destroy these tumor-killing T cells. If correct, that might suggest that limiting fungi while ensuring a healthy gut bacterial community could boost the immune system’s antitumor activities. The group is now conducting small trials in early-stage breast cancer patients on the effect of long-term antifungal use on radiation therapy outcomes.
“This work does have important potential translational implications, with the ability to target fungi in the gut microbiota to enhance responses to cancer treatment, though further studies need to be done to assess the relevance and translation of these findings in human cohorts,” writes Jennifer Wargo, oncologist and director of the Program for Innovative Microbiome and Translational Research at the University of Texas MD Anderson Cancer Center in Houston, in an email to The Scientist.
Shiao says the long-term goal of this research is “to develop the optimal microbiome composition—a mixture of some bacteria and some fungi that are the perfect balance—but we are trying to figure out what that is,” noting that it might be different depending on the situation and person. “Interventions for the microbiome are known and safe, so it could be translated pretty quickly,” he adds.