Researchers from the University of Michigan Health Rogel Cancer Center have uncovered a mechanism behind severe gastrointestinal issues associated with immune-based cancer treatment. Published in Science, their findings not only identified the cause of colitis induced by immune checkpoint inhibitors but also proposed an alternative therapy to maintain the cancer-killing impact while avoiding undesirable side effects.
Senior study author Gabriel Nunez, M.D., Paul de Kruif Professor of Pathology at Michigan Medicine, highlighted the significance of understanding mechanisms in developing more beneficial therapies. The team faced a challenge as laboratory mice didn’t exhibit colitis despite patients experiencing this side effect. Overcoming this, the researchers created a new mouse model by injecting microbiota from wild-caught mice, revealing that colitis development was linked to the gut microbiota’s composition.
The gut microbiota caused hyper-activation of immune T cells and the deletion of regulatory T cells within a specific domain of immune checkpoint antibodies, leading to colitis. By removing this domain, the researchers achieved a potent anti-tumor response without triggering colitis. This breakthrough underscores the essential role of microbiota in colitis development from immune checkpoint inhibition.
Nunez emphasized the novelty of their work in proving the critical role of microbiota in colitis induced by immune checkpoint inhibitors. The team is now planning further studies to deepen their understanding of the mechanisms behind colitis, with the aim of moving this knowledge into clinical trials in collaboration with clinical partners.
Source: University of Michigan