New research in mice has identified how gut bacteria alter the body’s response to PD-1 checkpoint blockade immunotherapy, currently used for the treatment of 25 forms of cancer.
The findings could inform the design of treatments that boost the efficacy of cancer immunotherapy among patients with suboptimal response.
The research by investigators at Harvard Medical School and Dana-Farber Cancer Institute found that specific gut bacteria can affect the activity of two immune molecules – PD-L2 and RGMb – as well as the interplay between them.
The work showed that blocking the activity of either molecule or the interplay between them enhanced responses to cancer immunotherapy and optimised the body’s ability to detect and destroy cancer cells.
The molecule RGMb was discovered to be a previously unknown accomplice in sabotaging the body’s ability to spot and destroy tumours. RGMb, primarily known for its role in nervous system development, is also found on the surface of cancer-fighting T cells. Until now, however, no one knew it played a role in regulating T-cell responses to cancer immunotherapy.
“Our findings offer a critical clue into a complex puzzle and in doing so suggest concrete ways to enhance the potency of cancer immunotherapy and improve patient outcomes,” said study co-first author Joon Seok Park, a postdoctoral research fellow in immunology in the lab of Arlene Sharpe, the Kolokotrones University Professor at Harvard and chair of the Department of Immunology in the Blavatnik Institute at HMS.
Sharpe co-led the research with Dennis Kasper, the William Ellery Channing Professor of Medicine and professor of immunology at HMS, and Gordon Freeman, Professor of Medicine at HMS and Dana-Farber.
How cancer evades immune defences
In the 1990s, Sharpe and Freeman performed some of the early work that explained how cancer evades the body’s immune system.
Their research showed that when PD-L1 or PD-L2 interact with another molecule, PD-1, on the surface of T cells, the activity of T cells is kept in check. Under normal conditions, this interaction functions as a brake on T cells to ensure they do not mistakenly attack the body’s own cells and tissues.
Sharpe, Freeman, and others discovered that cancer exploits this safety mechanism by expressing PD-L1 and PD-L2, engaging with PD-1 and reining in T cells.
The role of gut microbiota
In the new study, the researchers used mice whose colons were seeded with gut microbiota from patients with cancer. These animals’ response to immunotherapy mimicked the treatment response in the humans whose gut microbes now lived in their intestines.
Comparing the immune system profiles of the two groups of mice, the researchers identified tell-tale differences in various immune cells involved in cancer detection and destruction.
Mice seeded with gut microbes from patients that had themselves responded well to cancer immunotherapy had lower levels of PD-L2 on a class of immune cells known as antigen-presenting cells. Conversely, mice seeded with gut microbes from patients with a poor response to immunotherapy had increased levels of the PD-L2 molecule.
Further analyses showed that the interaction between RGMb and PD-L2 depended on the composition of gut microbes. The researchers found that certain gut microbes could affect the levels of both molecules.
Disabling the activity of either PD-L2 or RGMb was sufficient to preserve T cells’ antitumour activity and ensured a robust response to PD-L1 and PD-1 therapy. Blocking the activity of PD-L2 led to a potent antitumour response in animals treated with another form of immunotherapy, dendritic cell therapy.
The finding suggests that specific microbial molecules can be harnessed in the form of small-molecule drugs to augment the immune system’s ability to control cancer. Such treatments could supplement or be an alternative to traditional antibody-based cancer immunotherapy.
“This is likely only the beginning of the story,” said Francesca Gazzaniga, co-first author on the study and a former postdoctoral researcher in the Kasper lab. “Cancer, the immune system, and the microbiome are astoundingly complex individually, but when you put these systems together, the resulting interplay is exponentially more intricate.”