Gut bacteria boost cancer immunotherapy effects

About one in five cancer patients benefit from immunotherapy, a treatment that uses the immune system to fight cancer. This approach has shown significant success in the treatment of lung cancer and melanoma. Hoping for its potential, researchers are exploring strategies to improve immunotherapy for cancers that respond poorly to it, with the goal of helping more patients.

Now, researchers at Washington University School of Medicine in St. Louis have found that a strain of gut bacteria—Ruminococcus gnavus—can enhance the effects of cancer immunotherapy in mice. The study, published in Science Immunology, suggests a new strategy for harnessing gut microbes to unlock the untapped potential of immunotherapy in the fight against cancer.

“The microbiome plays an important role in mobilizing the body's immune system to attack cancer cells,” explained senior study author Marco Colonna, MD, PhD, Robert Roque Bellivou Professor of Pathology.

“Our findings shed light on one type of bacteria in the gut that helps an immunotherapy drug kill tumors in mice. Identifying such microbial partners is an important step in the development of probiotics that will help improve the effectiveness of immunotherapies and benefit more cancer patients."

Cancer immunotherapy uses the body's immune cells to target and destroy tumors. One such treatment uses immune checkpoint inhibitors to remove the natural brakes that keep immune T cells quiet, thereby preventing damage to the body. However, some tumors counter this by suppressing attacking immune cells, which reduces the effectiveness of such inhibitors.

Colonna and first co-author Martina Molgora, Ph.D., previously established a collaboration with colleague Robert D. Schreiber, Ph.D., in which they completely eradicated sarcomas in mice using a two-prong inhibition approach.

The researchers inhibited TREM2, a protein produced by tumor macrophages, to prevent T cells from attacking the growing tumor. They then showed that the immunotherapy drug was more effective when blocking TREM2. The result indicated that TREM2 reduces the effectiveness of immunotherapy.

In an experiment that became the basis for a new study, scientists made an unexpected observation. Mice without TREM2 showed a similar positive response to the checkpoint inhibitor when they lived with mice that had the protein. This result occurred when the researchers deviated from their usual protocol of separating mice before treatment with the inhibitor.

Mice living together leads to the exchange of microbes. The researchers suggested that the effects may be caused by the metabolism of gut bacteria.

The researchers worked with Jeffrey E. Gordon, M.D., and first co-author Blanda Di Lucia, Ph.D., to study the microbes in the guts of mice successfully treated with immunotherapy. They found an increase in the number of Ruminococcus gnavus compared with the absence of such microbes in mice that did not respond to therapy.

R. Gnavus was found in the gut microbiome of cancer patients who responded well to immunotherapy, Colonna explained. In clinical trials, fecal transplants from such patients helped some nonresponsive patients benefit from immunotherapy.

The researchers, including first co-author and graduate student Daria Khantakova, injected R. Gnavus into mice and then treated the tumors with a checkpoint inhibitor. Tumors shrank even when TREM2 was available as a weapon to reduce the effect of immunotherapy.

Gordon, director of the Edison Family Center for Genomic Sciences and Systems Biology, noted that growing evidence suggests that the microbiome enhances immunotherapy. Identification of relevant species, such as R. Gnavus, could lead to the development of a new generation of probiotics that could work in synergy with immunotherapy to improve cancer treatment.

Scientists now aim to understand how R. Gnavus promotes tumor rejection, which could reveal new ways to help cancer patients. For example, if a microbe produces an immune-activating metabolite during the digestion of food, this opens the possibility of using the metabolites as immunotherapy enhancers.

Microbes can also enter from the gut and trigger an immune response in the tumor or activate gut T cells, which then migrate to the tumor and launch an attack, Colonna explained. Researchers are exploring all three possibilities.