Why chronic gut inflammation can turn into colon cancer

The research centered on TL1A, an inflammatory signaling protein already known to be linked to both IBD and colorectal cancer. Drugs designed to block TL1A have shown strong results in clinical trials for IBD, but scientists had not fully understood how this protein drives inflammation and cancer development. In a study published in Immunity, the team showed that TL1A exerts much of its influence through a group of immune cells in the gut called ILC3s. When TL1A activates these cells, they draw large numbers of neutrophils, a type of white blood cell, from the bone marrow and alter their behavior in ways that promote tumor formation.

"These findings are important given the intense interest in the medical community to understand TL1A's role in IBD and its potential role in associated colorectal cancers -- for which we have had few strategies to mitigate the cancer risk," said study senior author Dr. Randy Longman, director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center and an associate professor of medicine at Weill Cornell Medicine.

Why IBD Carries a Higher Cancer Risk

IBD includes Crohn's disease and ulcerative colitis and is marked by long-lasting inflammation in the digestive tract. According to the U.S. Centers for Disease Control and Prevention, between 2.4 and 3.1 million Americans live with the condition. Beyond digestive symptoms, IBD increases the likelihood of other autoimmune and inflammatory disorders and sharply raises the risk of colorectal cancer. When cancer develops in people with IBD, it often appears at younger ages and is associated with poorer outcomes.

The researchers found that TL1A, which is mainly produced by immune cells already present in the inflamed gut, drives tumor growth largely through its effects on ILC3 cells. Once activated, these gut-resident cells release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that stimulates blood cell production. This signal sets off a process known as "emergency granulopoiesis" -- a rapid increase in neutrophil production in the bone marrow -- followed by the movement of these cells into the gut. In mouse models of intestinal cancer, the presence of these neutrophils alone was enough to accelerate tumor development.

Tumor-Promoting Changes in Immune Cells

Neutrophils are known to aid colorectal tumor growth by releasing reactive molecules that can damage DNA in the cells lining the gut. In this study, the team also discovered that ILC3 cells trigger a unique pattern of gene activity within the neutrophils. This pattern includes higher activity of genes linked to the start and progression of cancer. Similar gene expression changes were found in colon tissue samples from people with IBD-related colitis. Importantly, this tumor-promoting signature was less pronounced in patients who had received an experimental treatment that blocks TL1A.

New Targets for Treatment and Prevention

The findings suggest that several components of this immune pathway could serve as future treatment targets. In addition to TL1A itself, ILC3 cells, GM-CSF, and the neutrophils recruited by ILC3s may all play roles in strategies aimed at treating IBD while also lowering the risk of colorectal cancer.

"I think it will be exciting for clinicians in the IBD field to know that there is a systemic process at work here, involving both the gut and the bone marrow, with the potential to drive precision medicine in IBD," said study first author Dr. Sílvia Pires, an instructor in medicine and member of the Longman Laboratory.

What Researchers Are Studying Next

The team is continuing to investigate how this immune communication network functions during gut inflammation. Future work will explore whether early or occasional exposure to GM-CSF may prime bone marrow cells in ways that increase susceptibility to IBD over time, potentially opening the door to earlier intervention and prevention strategies.