Researchers may have uncovered a mechanism contributing to the development of colitis in patients with cancer receiving immunotherapy as well as a novel strategy to deliver immune-based therapy without causing the adverse side effect, according to a recent study published by Lo et al in Science.
Background
Immunotherapy has emerged as an effective treatment option for patients with several types of cancer, but immune checkpoint inhibitors can also cause severe side effects such as colitis—which can cause severe gastrointestinal discomfort and lead some patients to discontinue their cancer therapy. Although patients undergoing the therapy were developing colitis, laboratory mice were not, making it difficult to study what was causing this adverse side effect.
Study Methods and Results
In the study, the researchers created a new mouse model involving the injection of microbiota from wild-caught mice into the traditional mouse model. The researchers noted that the mice in the new model developed colitis following the administration of antibodies used for tumor immunotherapy—allowing them to better determine the mechanisms contributing to the reaction.
The researchers discovered that colitis may have developed in response to the composition of the gut microbiota, which caused immune T cells to become hyperactivated, whereas regulatory T cells responsible for inhibiting T-cell activation were deleted from the gut. They noted that this was occurring within a specific domain of the immune checkpoint antibodies. When the researchers removed this domain, they found that the mice still experienced strong antitumor activity without developing colitis.
To validate their findings from the mouse model, the researchers then reanalyzed previously reported data from studies of human cells in patients treated with immune checkpoint antibodies, which reinforced the role of regulatory T cells in inducing colitis.
Conclusions
“Previously, there were some data that suggested the presence of certain bacteria correlated with response to therapy; [however], it was not proven that microbiota were critical to develop colitis. This work for the first time shows that microbiota are essential to develop colitis from immune checkpoint inhibition,” emphasized senior study author Gabriel Núñez, MD, the Paul de Kruif Professor of Pathology at Michigan Medicine. “This is a good example of how understanding a mechanism helps … to develop an alternative therapy that’s more beneficial. Once we identified the mechanism causing the colitis, we could then develop ways to overcome this problem and prevent colitis while preserving the antitumor effect,” he highlighted.
The researchers plan to conduct further studies to better understand the mechanisms behind the development of colitis in this patient population.
Disclosure: The research in this study was funded by the National Institutes of Health, Takeda Millennium Pharmaceuticals, the Canadian Institutes of Health, the Crohn’s and Colitis Foundation, and the National Science Foundation; and supported by the University of Michigan Rogel Cancer Center Shared Resources: Single-Cell Spatial Analysis, Tissue and Molecular Pathology. For full disclosures of the study authors, visit science.org.
