August 26, 2021

Species of gut bacteria boosts response to cancer immunotherapy-and now we know why Using the bacteria to remodel' a patient's gut microbiota may improve efficacy of checkpoint inhibitors.

August 26, 2021

LA JOLLA, CA The key to more effective cancer treatments may be hiding in the gut. A new study led by Scripps Research scientist Howard Hang, PhD, explains how and why a certain species of bacteria in the digestive tract significantly improves the tumor-fighting ability of approved cancer drugs known as checkpoint inhibitors.

The discovery, based on observations in animals, could have a big impact on cancer care; checkpoint inhibitors have shown great success against many types of cancer, yet are unable to elicit much of a response among some patients.

Hang's findings, which appear in the journal Science, could lead to a new approach for boosting the effectiveness of cancer immunotherapies across a broader patient population and may help solve the molecular mystery of why certain people haven't benefited from the drugs.

His lab is now focused on new microbiota-based therapeutics, working closely with Calibr, the drug development division of Scripps Research, to translate the science into a potential medicine that can be taken in combination with checkpoint inhibitors. They are also exploring whether the approach could help boost the body's immune response to other disease threats, including the virus that causes COVID-19.

Some bugs' boost the immune system

As Hang explains, every person has many thousands of species of bacteria and other microorganisms living in his or her gut, comprising what is known as the gut microbiome. Over the last decade, Hang and other scientists have sought to learn which species of bacteria are beneficial to our health and which are bad. But it's not always a simple distinction.

A species that had been considered as possibly harmful is enriched in patients that respond better to checkpoint inhibitor immunotherapies, says Hang, who joined Scripps Research in July as a professor in the departments of Immunology & Microbiology and Chemistry. That led us to investigate why that's happening and how we could harness those effects in the patients who aren't responding to the therapies.

The bacteria at the center of the study are part of a genus is known as Enterococcus. Certain species of this genus are common in the gut and have been developed as probiotics. However, antibiotic-resistant and pathogenic strains also are known to cause dangerous infections in humans and animals. In experiments conducted primarily at The Rockefeller University, where Hang previously served as professor, he and his team sought to learn how these bacteria improve responses to the cancer drugs.

If you understand the mechanism, you may be able to create a way to replicate it, Hang says. We wanted to know how these bacteria were influencing the immune system.

From discovery to a potential treatment

Hang's team found that several species of Enterococcus encode a unique secreted enzyme that digests bacterial cell wall fragments. These microbial metabolites, known as peptidoglycans, can disseminate into the bloodstream and prime the immune system to fight tumors or infections.

The scientists showed that by administering these bacteria in conjunction with a promising class of cancer drug known as checkpoint inhibitors, the drugs worked more effectively in mice. Checkpoint inhibitors are designed to activate the patient's immune system to attack tumors, getting around the checkpoints that cancer cells use to avoid detection. To circumvent the potential antibiotic-resistant and pathogenic properties of Enterococcus, the Hang laboratory collaborated with scientists at Rise Therapeutics and engineered probiotic bacteria to make this unique peptidoglycan digesting enzyme, which also enhanced the efficacy of immune checkpoint inhibitors in mouse tumor models.

Hang's experiments specifically looked at a cancer immunotherapy that targets proteins known as PD-L1 as well as CTLA-4, which enables cancer cells to hide from the immune system. Anti-PD-L1 and CTLA-4 drugs have shown great success against many forms of cancer, but patient responses can vary greatly for a number of factors some known and some unknown.

By finally understanding why certain gut microbes, specific enzymes and metabolites produced by microbes are boosting the effects of checkpoint inhibitors, Hang hopes to lay the groundwork for more reliable patient outcomes. This work was spearheaded by a postdoctoral researcher in the Hang laboratory, Matthew Griffin, PhD, who has also moved to Scripps Research to continue these exciting studies.

We now plan to leverage these findings in our laboratory, and in collaboration with Calibr, to create new types of adjuvants that can make checkpoint inhibitors even better at fighting tumors and more effective across larger patient populations, he says. This is a prime example of how basic research led to a discovery with potential for enormous human impact.

Further dissecting microbiota and pathogen mechanisms

Given the significance of Enterococcus interactions with host immunity and immunotherapy, Hang and colleagues have now harnessed the revolutionary CRISPR gene editing technology to efficiently generate new genetic variants of the specific Enterococcus species. The new findings appear in the journal Applied and Environmental Microbiology. Their significantly improved genetic methods should allow Hang and colleagues to further elucidate immune modulation mechanisms as well as identify new antibiotic targets in pathogenic strains of Enterococcus, which have emerged as major healthcare associated infections.

The study, Enterococcus peptidoglycan remodeling promotes immune checkpoint inhibitor therapy, is authore

LINK:	https://www.scripps.edu/news-and-events/press-room/2021/20210826-hang-...
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