How Diet And Probiotics Could Make Cancer Immunotherapy More Effective
The gut microbiome plays a critical role in determining the effectiveness of immunotherapy in cancer treatment, which enhances the body’s immune system to detect and eradicate cancer cells. Nonetheless, this therapy is successful in certain patients but not in others.
Several recent investigations have identified a correlation between probiotic supplements and the response to immunotherapy in melanoma patients.
To delve deeper into this link, Meisel and her team administered L. reuteri, a bacterium that is commonly found in probiotic products, to germ-free mice with melanoma. They demonstrated that the bacteria migrated from the gut to the tumors, where they colonized and survived for a prolonged period.
When compared to the mice in the control group that did not receive any bacteria, those that were given L. reuteri had a more substantial quantity of powerful CD8, also known as “killer,” T cells at the tumor site. The tumors in these mice shrunk more, and their life expectancy increased. Furthermore, the effects of L. reuteri were not exclusive to melanoma. In mouse models of adenocarcinoma, fibrosarcoma, and breast cancer, the bacterium migrated to tumors beyond the gut and hindered cancer growth similarly.
Upon further investigation, they discovered that L. reuteri encourages immunity in tumors by generating I3A, which triggers a receptor in CD8 cells. Even though this receptor is present in almost every cell in the body, I3A has a specific impact on CD8 cells, enhancing their ability to destroy cancer cells. When the researchers removed the receptor in these cells, the bacteria could no longer prompt anti-tumor immunity, indicating that the effect is reliant on this receptor in CD8 T cells. Using a genetically modified variant of L. reuteri that cannot produce I3A, the researchers demonstrated that this compound is crucial for the bacterium’s impact on boosting anti-tumor immunity and suppressing tumor growth.
“While the microbiome of tumors beyond the gut, including melanoma, had been described, the concept that tumor microbes play an active role in mediating cancer immunotherapy efficacy had not been demonstrated,” adds Meisel. “So, we were surprised to find that I3A released by L. reuteri within the tumor enhanced immunotherapy response whereas the presence of L. reuteri in the gut was insufficient to have an anti-tumor effect.”
In an effort to determine whether I3A could play a role in human response to immunotherapy, Meisel partnered with Diwakar Davar, M.D., an assistant professor of medicine at Pitt and member of the CIIP, and Hassane Zarour, M.D., a professor of medicine at Pitt and co-leader of the CIIP. In previous research, they discovered that modifying gut bacteria via fecal transplants improved immunotherapy response in melanoma patients.
After examining blood samples from melanoma patients receiving immune checkpoint inhibitor therapy, they discovered that patients who responded well to immunotherapy had higher levels of I3A. They also observed that higher I3A levels before treatment were associated with a higher chance of survival.
“Building on these findings in the future, it might be possible to use I3A levels as a biomarker to predict which patients are likely to respond to immunotherapy,” points out Meisel. “Another direction I’m excited about is developing clinical trials to evaluate whether combining I3A with immunotherapy could improve outcomes for patients.”
To produce I3A, L. reuteri requires tryptophan, an amino acid present in foods such as soybeans, oatmeal, nuts, seeds, and chicken. When mice with melanoma were fed a diet high in tryptophan, their tumors grew at a slower rate, and they lived longer than the control mice that received an otherwise similar diet that was low in tryptophan. A diet rich in tryptophan also boosted the impact of immunotherapy in reducing tumor size.
Meisel emphasized that further research, including rigorously controlled clinical trials, is necessary to ascertain whether a tryptophan-rich diet could have an impact on cancer patients’ outcomes.
Meisel stated that this paper should not be taken as a recommendation, but rather as a starting point to encourage further research into how diet can affect immunity and cancer outcomes. She added that her laboratory is exploring whether holistic approaches, such as dietary or lifestyle modifications, could improve the efficacy of immunotherapy and other cancer treatments. Meisel believes that it is empowering for patients to have the ability to make these changes themselves, with careful clinical consideration, and to have some influence over their treatment journey rather than being entirely dependent on the healthcare system.
The findings were published today in Cell.
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