Putting the brakes on chronic inflammation

Scientists at Weill Cornell Medicine have uncovered a previously unknown connection between two key pathways that regulate the immune system in mammals, offering new insights into chronic inflammatory bowel diseases (IBD) and the side effects of cancer immunotherapy. The study, published in Nature, reveals that interleukin-23 (IL-23), an immune factor implicated in various autoimmune diseases, interacts with group 3 innate lymphoid cells (ILC3s) to increase the activity of CTLA-4, a critical regulatory factor that prevents the immune system from attacking the body and beneficial gut microbiota.

The discovery of this interaction between IL-23 and ILC3s helps explain why IL-23 can be both beneficial and detrimental, depending on the context. In the healthy gut, IL-23 provides tissue protection, but in chronic inflammatory diseases, it becomes a key driver of tissue pathology. The study’s senior author, Dr. Gregory Sonnenberg, expressed surprise at uncovering the unexpected connection between these two major immune pathways that control health, immunity, and inflammation.

Investigating the Role of IL-23 in Inflammatory Bowel Diseases

To investigate the changes that occur in chronic inflammatory diseases, the study’s lead author, Dr. Anees Ahmed, and his team used single-cell RNA sequencing to study the effects of IL-23 on different types of immune cells in the healthy intestine. They discovered that IL-23 potently activates the CTLA-4 pathway in ILC3s and that blocking this pathway led to severe intestinal inflammation.

The researchers then confirmed the relevance of their findings in human samples, utilizing the Jill Roberts Institute Live Cell Bank, which includes deidentified samples from both IBD patients and healthy individuals. In collaboration with Dr. Robbyn Sockolow, a pediatric gastroenterologist at Weill Cornell Medicine and NewYork-Presbyterian Komansky Children’s Hospital and Center for Advanced Digestive Care, they found evidence that this novel immunologic pathway exists in the healthy human intestine but becomes impaired in the inflamed intestine of IBD patients.

Harnessing the IL-23-ILC3s Pathway in Cancer Immunotherapy

The study’s findings also have implications for cancer treatment and the side effects associated with certain immunotherapy drugs. Immunotherapy drugs that block CTLA-4 are used to unleash the immune system’s ability to fight cancer, but these new results suggest that CTLA-4 on ILC3s and other related innate or innate-like lymphocytes should be considered in this context. Moreover, blocking CTLA-4 on ILC3s may lead to severe gut inflammation, causing patients to discontinue their cancer treatment.

While much more research is needed before these findings can be translated into new treatments, Dr. Ahmed suggests that it may be possible to develop more targeted therapies that avoid ILC3s in the gut or simultaneously block IL-23. “If we could manage it, that could lead to a breakthrough in fighting cancer while protecting the gut from inflammation,” he said.

The study’s findings could also have long-term applications in developing new treatments for a range of autoimmune diseases known to be mediated by IL-23. Dr. Sonnenberg noted that existing drugs targeting IL-23 could potentially be improved by controlling the underlying mechanisms of IL-23–driven chronic inflammatory diseases, rather than completely blocking IL-23, which is still needed to fight infection.

“We were surprised to uncover the unexpected connection between these two major immune pathways that control health, immunity and inflammation,” said Dr. Sonnenberg. “Until now most research on CTLA-4 focused on T cells, another type of immune cell. By uncovering that it is selectively upregulated on ILC3s by IL-23, this demonstrates that we should be thinking about these pathways more broadly to develop more selective therapeutics.”

The discovery of this novel link between IL-23 and ILC3s in regulating the immune system opens up new avenues for understanding and treating chronic inflammatory bowel diseases, as well as improving cancer immunotherapy while minimizing its side effects.

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