Gut Bacteria Compound Boosts Cancer Immunotherapy in Mice, Study Finds

A compound made by gut bacteria as they break down dietary fiber may offer a way to strengthen cancer immunotherapy, according to University of Michigan researchers. The team turned the compound, 3,4-dihydroxybenzoic acid, or DHB, into an oral drug and tested it in mice. The work was published in the journal Nature Nanotechnology.

The approach targets a limitation of immune checkpoint blockade, a cancer treatment that releases the immune system's natural brakes so T cells can recognize and destroy cancer cells. Although checkpoint therapies have transformed cancer treatment, patient response rates are often low, partly because T cells gradually lose their ability to kill cancer cells and stop dividing.

Screening compounds made by gut microbes, the researchers found that DHB encouraged T cells to develop into memory T cells, which multiply rapidly and play a central role in sustaining antitumor immune responses. Naturally occurring DHB is poorly absorbed by the body and quickly removed, so the team enclosed it in a protective nanoemulsion shell and converted it into an inactive precursor that becomes active only after reaching its target tissue.

In mouse models of melanoma, colorectal cancer and breast cancer, tumors were eradicated when the oral prodrug was given together with immune checkpoint blockade therapy. The treated mice also developed long-term immune memory that prevented their tumors from returning. James Moon, a professor of pharmaceutical sciences at Michigan's Rogel Cancer Center who worked on the study, said DHB also improved the effectiveness of CAR T-cell therapy, which re-engineers a patient's own immune cells to target cancer.

"This is the first time anyone has shown that natural microbial metabolites can be developed as a new oral formulation for immunotherapy," Moon said. The researchers are now screening additional gut-microbial compounds and hope the nanomedicine methods developed for this work could eventually help treat autoimmune diseases as well. They said they hope the results seen in mouse tumor models will also hold true in human clinical trials.