Making the microbiome more amenable to cancer immunotherapy

The gut microbiome—the collection of bacteria, viruses, fungi, and other microorganisms that reside in our gastrointestinal tracts—can impact us in a variety of different ways, from our metabolism to our mood. Research also suggests that the gut microbiome can modulate the immune system, such as affecting responses to pathogens. Emerging evidence has also shown that imbalances in the gut microbiome can affect responses to certain cancer treatments.

Now, NIBIB-funded researchers are investigating if a fiber-based gel can restore beneficial microbes in the gut to enhance the efficacy of immune checkpoint inhibitors, a type of cancer immunotherapy treatment.

“The gut microbiome is an emerging area of scientific discovery, and we are beginning to understand how changes to this complex ecosystem can affect human health and disease,” said David Rampulla, Ph.D., director of the division of Discovery Science & Technology at NIBIB. “This study is a promising example illustrating that biomaterials could be used to modulate the gut microbiome, regulating immune responses and potentially augmenting existing cancer treatments.”

Cancer immunotherapy is a type of treatment that recruits our own immune system to help recognize and attack cancer cells. The most common type of cancer immunotherapy is a treatment known as an immune checkpoint inhibitor, which blocks interactions on immune cells that would otherwise hinder their ability to kill cancer cells. While this approach has revolutionized cancer treatments, only a minority of patients respond to this type of therapy. What’s more, research indicates that patients with imbalances in their gut microbiome may be less likely to respond to this treatment.

Many research labs are pursuing ways to manipulate the gut microbiome to enhance cancer immunotherapy, including the oral ingestion of probiotics or fecal microbiota (stool) transplantation, explained James Moon, Ph.D., the John G. Searle Professor of Pharmaceutical Sciences and Biomedical Engineering at the University of Michigan. His lab is pursuing an alternative approach by developing a colon-retentive gel made of inulin—a widely-consumed dietary fiber—that can modulate the gut microbiome to improve responses to cancer immunotherapy.

Inulin is a prebiotic—that is, a nondigestible substance that “feeds” healthy bacteria in the gut, thereby selectively stimulating beneficial microbes in the gastrointestinal tract. Inulin, which is widely available, is found in many fruits, vegetables, and herbs, and research has shown that inulin can increase the growth of favorable bacteria in the human gut. Building on this knowledge, the researchers investigated whether inulin could enhance responses to an immune checkpoint inhibitor in multiple mouse models of cancer.

In their study, recently reported in Nature Biomedical Engineering, the researchers found that tumor-bearing mice given inulin plus an immune checkpoint inhibitor had reduced cancer growth and increased survival when compared with mice that received the immune checkpoint inhibitor alone. The researchers also evaluated how these treatments affected the gut microbiome of the mice. Compared with the immune checkpoint inhibitor alone, the combined treatment significantly increased the levels of several types of beneficial bacteria—some by over 15-fold—that have been associated with a favorable response to this type of immunotherapy among patients with cancer. Further, treatment with the immune checkpoint inhibitor alone actually decreased the level of one type of beneficial bacteria by almost 100 percent, but the inulin treatment was able to partially restore the bacteria.

Next, the researchers wanted to investigate if prolonged exposure of inulin in the gut could further amplify its effect. They developed an inulin gel, which is administered orally, but is viscous and likely coats the lining of the colon in the mice. Compared with tumor-bearing mice treated with an immune checkpoint inhibitor and unmodified inulin, mice that were treated with an immune checkpoint inhibitor plus the inulin gel had markedly delayed tumor growth and increased survival.

The researchers also looked at how the combined treatment of inulin gel and the immune checkpoint inhibitor affected the immune system of the mice. They found that this treatment enhanced responses of antitumor T cells (white blood cells that can attack cancer cells).

“In this study, we have engineered a biomaterial that targets and manipulates favorable bacteria in the gut, which we found to enhance cancer immunotherapy treatment in mice,” Moon said. “Our colon-retentive inulin gel may provide an approach for restoring a healthy gut microbiome in patients with cancer in the future.”

Moon highlighted the preclinical nature of his work, and noted that his lab is planning to examine the safety and microbiome-modulating effects of their inulin gel in healthy volunteers, which could be followed by a clinical trial in patients with cancer.

It is important to note that while many commercial dietary supplements exist, the U.S. FDA does not have the authority to review dietary supplement products for safety and effectiveness before they are marketed. Talk with your healthcare provider before making decisions about whether to take dietary supplements.

This study was funded by grant R01EB022563 from the National Institute of Biomedical Imaging and Bioengineering (NIBIB); grant R01AI127070 from the National Institute of Allergy and Infectious Diseases (NIAID); grants R01CA210273, U01CA210152, P30CA046592, R01CA227622, R01CA222251, and R01CA204969 from the National Cancer Institute (NCI); and grant R01DK125087 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Study reference: Han, K., Nam, J., Xu, J. et al. Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-021-00749-2

This Science Highlight describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process — each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.