According to a new study by researchers from the Center for Cancer Research at the National Cancer Institute (NCI), part of the National Institutes of Health and the MD Anderson Cancer Center at the University of Texas. The results of the study, which analyzed both people with melanoma and mouse models of the disease, appear in Science.
Among patients with advanced melanoma who underwent immunotherapy with immune checkpoint blockers, those who consumed at least 20 grams a day of dietary fiber survived the longest without their disease progressing. In contrast, the use of probiotic supplements appears to somewhat decrease the effectiveness of immune checkpoint blocking diets. Probiotics are live microorganisms typically taken as a supplement to improve gut health.
“The data suggest that one can target the composition of the gut microbiota and affect the patient’s ability to respond to immunotherapy,” said Giorgio Trinchieri, MD, head of the Integrative Cancer Immunology Laboratory at the Center for Cancer Research. NCI Cancer, one of the study’s co-leads. “Eating a diet high in fiber, such as fruits, vegetables and legumes, may improve your ability to respond to immunotherapy.”
Immunotherapy with immune checkpoint blockers helps restore the immune system’s natural ability to recognize and kill tumor cells. These drugs have transformed melanoma, improving the lifespan of some people with advanced disease, sometimes by years. However, for many patients, immune checkpoint blockers fail to stop their tumors from growing. Several studies have suggested that the composition of bacteria in the gut may influence the response to immunotherapy.
“The question is, can we change the composition of the type of bacteria in the gut and improve the patient’s ability to respond?” said Dr. Trinchieri.
In a previous study, Dr. Trinchieri and another group of collaborators showed that some people with melanoma who initially did not respond to treatment with an immune checkpoint blocker responded after receiving a fecal transplant from a patient who had responded to the drug. The fecal transplant, they concluded, introduced different gut bacteria that made it easier for immune cells to invade and kill their tumors.
“Dietary fiber intake and the use of probiotic supplements have also been shown to affect the composition of gut bacteria. More and more cancer patients are taking probiotic supplements in an effort to improve their gut health, but little is known about how probiotics – which fundamentally alter the ecology of gut bacteria – impact the immunotherapeutic response,” he said.
The link between fiber intake and immunotherapeutic response is also unclear. However, a recent study by Romina Goldszmid, Ph.D., also of the NCI Cancer Research Center, showed that mice fed a diet high in pectin, which is a fiber abundant in apples, were able prevent tumor growth by activating immune cells and reprogramming the tumor microenvironment.
In the new study, Dr. Trinchieri and study co-leads Carrie R. Daniel, Ph.D., MPH, and Jennifer A. Wargo, MD, of the University of Texas MD Anderson Cancer Center, and their collaborators examined the composition of faecal microorganisms (the gut microbiota), dietary habits and use of probiotic supplements in patients treated for advanced melanoma with immune checkpoint blockers.
Among the 128 patients whose dietary fiber intake was known, those who reported consuming at least 20 grams of dietary fiber daily (an amount the researchers called “enough” for the purposes of this study) lived longer without that their cancer progresses only those who consume less dietary fiber. Each 5 gram increase in daily dietary fiber intake corresponded to a 30% decrease in the risk of disease progression.
The researchers also looked at the impact of dietary fiber on response to treatment with anti-PD-1 drugs, a class of immune checkpoint blockers, in mouse models of melanoma. To mimic the different diets of melanoma patients, they fed the mice a high-fiber or low-fiber diet, injected the mice with melanoma cells, and then treated the mice with anti-PD-1 therapy. . Mice given the high-fiber diet had delayed tumor growth after anti-PD-1 treatment, compared to mice given the low-fiber diet.
The researchers then repeated the experiments on germ-free mice, that is, mice that do not have bacteria in their intestines.
“In germ-free mice, diet made no difference in immunotherapeutic response,” Dr. Trinchieri said. “This suggests that diet affects the response to immune checkpoint therapy by altering the composition of the gut microbiota.”
Dr. Trinchieri noted that one possible mechanism by which dietary fiber exerts its beneficial effect is by increasing the types of bacteria in the gut, such as Ruminococcaceae, that produce high levels of certain short-chain fatty acids that have an antitumor effect.
“We found an increase in one of these short-chain fatty acids, propionate, in mice fed a high-fiber diet,” Dr. Trinchieri said. “Furthermore, patients whose cancer responded to immunotherapy had a higher abundance of Ruminococcaceae bacteria in their gut microbiota compared to those who did not respond to treatment.”
The researchers also looked at the impact of probiotics on gut bacteria in the mouse model of melanoma. Mice fed probiotics had a reduced response to treatment with anti-PD-L1 drugs and developed larger tumors than control mice. Further analysis showed that mice fed probiotics had lower levels of tumor-killing immune cells, suggesting a weakened immune response.
In the human study, nearly a third of patients reported taking a probiotic supplement in the previous month. Although the researchers noted that the small sample size and variety of probiotics used by patients made it difficult to draw firm conclusions about the association between probiotic use and response to immune checkpoint blockers , they observed that patients who consumed the highest levels of dietary fiber without the use of probiotics survived the longest.
“The impact of dietary fiber and probiotics on gut microbiota is only part of the bigger picture,” Dr. Trinchieri warned. “Many factors can affect a melanoma patient’s ability to respond to immunotherapy. However, from these data, the microbiota seems to be one of the dominant factors. The data also suggests that it is probably best for people with cancer receiving immunotherapy not to use commercially available probiotics.
He noted that larger studies are warranted and should include cancers other than melanoma.
About the National Cancer Institute (NCI): The NCI leads the National Cancer Program and NIH efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families through research in cancer prevention and biology, the development of new interventions and the training and mentoring of new researchers.
About the National Institutes of Health (NIH): The NIH, the country’s medical research agency, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases.