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Gut Microbiota Emerging as Key Player in Response to Immunotherapy


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The microbiome—and the foods that feed it—is emerging as an important determinant of a patient’s response to immunotherapy. Much of the research in this area comes from The University of Texas MD Anderson Cancer Center, as described at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium by Jennifer Leigh McQuade, MD, Assistant Professor of Melanoma Medical Oncology there.1

Jennifer Leigh McQuade, MD

Jennifer Leigh McQuade, MD

“The role of the host in determining immune response has not been previously well studied,” said Dr. McQuade. “We know that immunity varies among individuals and can be influenced by factors such as age and sex, but now we’re seeing unexpected associations in the way that these factors may influence immunotherapy response.”

At the Symposium, Dr. McQuade discussed the role of specific bacteria, fecal microbiota transplants, and certain foods on systemic and antitumor immunity.

The Microbiome and Immunity

As Dr. McQuade reported, there is an existing body of literature concerning how modifiable factors, such as obesity, diet, exercise, stress, and sleep, influence immune response in other contexts. The “very intimate relationship between the gut microbiome and the immune system” has been previously studied in the context of colorectal cancer and autoimmune diseases, said Dr. McQuade. And the association between gut microbiome diversity and stem cell transplant outcomes is important to consider in the context of immunity.

Although landmark studies have demonstrated that gut microbes could influence response to immunotherapy in mice,2,3 the relevance to humans remains uncertain. Nevertheless, added Dr. McQuade, there is a growing body of evidence. An analysis of fecal specimens taken from patients initiating immunotherapy found an association between higher diversity in the gut microbiome and improved progression-free survival with immunotherapy and pro-response bacteria correlated with a T-cell–inflamed tumor microenvironment.4

What’s more, the same researchers showed that responsiveness to immunotherapy can be transmitted via fecal microbiota transplants from humans to mice. Mice that received fecal transplants from human responders also responded to immunotherapy, whereas mice that received transplants from human nonresponders did not.

“This is a really important proof of principle in mice,” said Dr. McQuade. “There are now multiple ongoing studies testing this within humans, doing fecal microbiota transplants in patients who are receiving immunotherapy.”

Certain Diets and Bacteria More Impactful Than Others

According to Dr. McQuade, one of the most exciting elements of the gut microbiome is that it is inherently modifiable. Less than 10% of the gut microbiome is genetically determined, and potentially modifiable factors may play a key role in determining the profile.

“There are well-described associations between specific dietary factors, different gut bacteria that help us digest those foods, and then downstream microbial metabolites,” said Dr. McQuade. “An MD Anderson study found fiber-fermenting bacteria to be associated with immunotherapeutic responses, whereas Akkermansia muciniphila, identified in a French cohort, seems to be associated with a very prototypical French diet full of coffee, wine, chocolate, and nuts,” as shown by Routy et al.5 In their 2018 study, metagenomics of stool samples from patients with cancer at diagnosis revealed correlations between clinical response to checkpoint inhibitors and the relative abundance of Akkermansia.5

The Importance of Fiber

As Dr. McQuade explained, the link between dietary fiber and immunity is short-chain fatty acids. They are produced by fiber-fermenting bacteria and are the primary nutrient source for gut enterocytes. The bacteria then help form a thick mucosal barrier in the gut.

“Fiber is a prebiotic and essentially a food source for these bacteria,” said Dr. McQuade, who noted that the interaction between fiber-fermenting bacteria, short-chain fatty acids, and mucosal immunity has been well studied. “We’re also starting to see some data emerging on how this might influence systemic immunity, with epigenetic changes leading to memory T-cell differentiation.”

What’s less known, however, is how dietary fiber might influence antitumor immunity. Dr. McQuade and colleagues have been collecting gut microbiome samples and asking their patients about their diet and lifestyle. What they’ve found is consistent with studies of healthy populations.

“Patients who are eating more fiber, fruits, vegetables, and whole grains have an increased abundance of these pro-response, fiber-fermenting bacteria,” she observed. “More importantly, patients who consume a high-fiber diet as a habitual diet were nearly five times more likely to respond to programmed cell death protein 1 (PD-1)-based immunotherapy and had significantly improved progression-free survival.”

The researchers also studied the synergy between the gut microbiome signature and dietary fiber intake. They found that patients most likely to respond to immunotherapy are those who have both “good bacteria” and a fiber-rich, plant-based diet needed to feed those bacteria. According to Dr. McQuade, these findings have important implications for fecal microbiota transplant studies—namely, how to sustain this new microbiome once it’s been transplanted.

“We’ve seen that we can very quickly shift the gut microbiome in mice by modulating dietary fiber,” said Dr. McQuade.

Mice that receive a low-fiber diet, for example, have tumors that fail to respond to immunotherapy, and researchers have observed distinctions in the immune infiltrates. When this experiment is repeated in germ-free mice, on the other hand, that distinction disappears.

“These findings implicate the microbiome as actually being the mediator in this relationship between dietary fiber and response to immunotherapy,” she observed.

Diet as Precision Intervention in Cancer

Whether the gut microbiome can be as quickly modulated with dietary fiber in humans remains to be seen, but early research is promising. A 2-week controlled feeding study of “swapping” Northern African and African American diets found evidence that changes in the diet can have a profound impact on the microbiome in a short time.6

“When North Africans, who were accustomed to eating a plant-based diet, switched to eating fast food, their capacity for fiber fermentation went way down,” said Dr. McQuade. “The exact reciprocal changes occurred in the African Americans now eating abundant fiber: Fiber-fermenting bacteria increased significantly.”

Researchers at MD Anderson are testing the hypothesis that unprocessed, plant-based, and fiber-rich foods will modulate the microbiome and enhance systemic and antitumor immunity. In early unpublished experiments, they have found that adding one cup of beans per day (16 g of fiber) to the usual diet of patients with colorectal cancer will increase the amount of fiber-fermenting Faecalibacterium; conversely, when the diet is stopped, the amount of that bacteria decreases.

“We have to sustain dietary changes to sustain microbiome changes,” noted Dr. McQuade.

Modulation of Microbiome and Immune Response

The next step for Dr. McQuade and colleagues is to see whether modulation of the microbiome with a controlled feeding study can actually change immune response. Patients with cancer will be randomly assigned to either a high-fiber diet (50 g of fiber per day) with diverse whole grains, fruits, and vegetables or a standard healthy diet recommended by the American Cancer Society. Foods will be prepared and provided to the patients. The researchers will then longitudinally profile the gut microbiome and measures of systemic and antitumor immunity, and ultimately disease outcomes, in the context of treatment with antibodies against PD-1.

In the meantime, as Dr. McQuade and colleagues establish the effects of dietary intervention on the structure and function of the gut microbiome, many patients may be tempted simply to take a probiotic to achieve the same result. According to Dr. McQuade, however, there may not be a shortcut to a healthy gut.

“Approximately 42% of our patients were taking probiotics when we surveyed them,” she said. “Those taking probiotics had lower diversity of their gut microbiome, were less likely to respond to immunotherapy, and had impaired progression-free survival.”

“This is correlation not causation, but there are other supporting data suggesting that nonselected, over-the-counter probiotics might actually interfere with the function of our normal gut microbiota,” Dr. McQuade concluded. “Changing one’s diet is difficult, but it may be necessary for immune response.” 

DISCLOSURE: Dr. McQuade is on the advisory board of Bristol-Myers Squibb and Roche and is a paid consultant for Merck.

REFERENCES

1. McQuade JL: Impact of diet and other factors on the microbiota and responses to therapy. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Invited Lecture. Presented February 8, 2020.

2. Sivan A, Corrales L, Hubert N, et al: Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084-1089, 2015.

3. Vétizou M, Pitt JM, Daillère R, et al: Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:1079-1084, 2015.

4. Gopalakrishnan V, Spencer CN, Nezi L, et al: Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359:97-103, 2018.

5. Routy B, Le Chatelier E, Derosa L, et al: Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:91-97, 2018.

6. O’Keefe SJD, Li JV, Lahti L, et al: Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun 6:6342, 2015.


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