Inflammatory Bowel Disease (IBD) is a chronic disease of inflammation along the digestive tract. There are two forms of IBD, including Crohn’s disease and ulcerative colitis. Symptoms include abdominal pain, weight loss, fatigue, and sometimes blood in the stool. While there is no cure, it is important to manage symptoms with anti-inflammatory medications, immune suppressants, and altered diet. In extreme cases, surgery may be necessary. However, uncontrolled symptoms can lead to more serious conditions, such as cancer.
IBD has previously been associated with colorectal cancer (CRC). Unfortunately, patients with IBD have increased risk of CRC due to chronic gut inflammation. Prevalence increases the longer a patient has IBD, since inflammation can cause mutations that drive malignancy. It is critical that IBD is controlled and monitored through annual colonoscopies and strict management of symptoms. While inflammation is known to cause cancer, the exact underlying mechanism is unclear. Scientists are currently working to further understand this correlation and develop therapies that can help prevent CRC in patients with IBD.
A recent article in Immunity, by Dr. Randy Longman and others, demonstrated that immune reactions in the gut driven by protein signaling and white blood cell function increase the risk of CRC in patients with IBD. Longman is a physician scientist and Director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. As a gastroenterologist and mucosal immunologist, Longman focuses on understanding the causes of IBD. His work tries to develop new therapies and improve standard-of-care treatment.
Longman and his group focused on an inflammatory immune signaling protein associated with IBD and CRC, known as TL1A. Drugs that block this protein have shown promise for patients with IBD in clinical trials. Therefore, the team looked at how TL1A inhibition improves patient outcomes. Through animal models of IBD, TL1A was linked to specialized immune cells referred to as ILC3s. These cells were activated by TL1A and generated a chain reaction to attract other immune cells, neutrophils, to the cite of inflammation. These neutrophils from the bone marrow were dysregulated due to ILC3 activation.
How neutrophil-driven tumor progression occurs is of great scientific interest. CRC is not the only cancer that has been reported to produce tumor-promoting neutrophils. Therefore, this mechanism may be applied to other cancer types for treatment. The team discovered that TL1A drives this process by activating ILC3s. In turn, these cells produce a protein known as granulocyte-macrophage colony-stimulating factor (GM-CSF). The massive production of GM-CSF generated an emergency response that produced neutrophils. These dysregulated neutrophils then secrete proteins and other molecules to make an environment habitable for tumors and toxic for healthy immune cells.
Longman and others have identified a cellular mechanism that explains why IBD patients have higher risk of CRC. Consequently, proteins and cells such as TLA1, ILC3s, and neutrophils all have the potential as therapeutic targets to enhance current treatments. Researchers hope that this discovery will lay the foundation for improved clinical therapies. Overall, these findings will improve diagnostic strategies, symptom monitoring, and standard-of-care treatment.
Article, Randy Longman, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine