Researchers at the University of Galway have made a world-first breakthrough in understanding how bowel cancer evades the immune system, discovering that tumor cells use a "sugar shield" to deactivate the body's natural cancer-fighting defenses. The findings, published in the Journal for ImmunoTherapy of Cancer, reveal a previously unknown mechanism that could explain why immunotherapy has shown limited success in bowel cancer compared to other malignancies.
Sugar-Coated Stromal Cells Suppress Immune Response
The research team, led by Professor Aideen Ryan from the University's College of Medicine, Nursing and Health Sciences, focused on stromal cells within bowel tumors. While these are normal supportive tissue cells, they become heavily coated with sugar molecules called sialoglycans in the tumor environment. This hypersialylation creates a molecular disguise that interacts with receptors called siglecs on immune cells, effectively switching off the body's natural defense mechanisms.
"This world-first finding shows that some of the bowel cancer cells are not just passive bystanders, they are actively reprogramming the body's immune cells, preventing them from doing their job," said Ryan. The study demonstrated that this sugar coating specifically targets two critical immune cell types: natural killer (NK) cells and macrophages, rendering them inactive and unresponsive to immunotherapy.
Blocking the Sugar Shield Reactivates Immune Defenses
Using bowel cancer tissue samples and mouse models, the researchers tested two approaches to disrupt this immune suppression mechanism. They either blocked the sialylation enzyme ST6GALNAC6, which adds sialic acids to cells, or used enzymes called sialidases to remove the sugar coating entirely.
The results were striking. When the sugar shield was removed, macrophages regained their ability to engulf and destroy cancer cells, while NK cells became aggressive again and began producing attack proteins. Tumor growth slowed, cancer spread was prevented, and immune activity increased throughout the body. The researchers found that stromal cells had much higher levels of sialic acids than regular cancer cells, and this hypersialylation was linked to worse survival outcomes for patients.
New Therapeutic Targets Identified
The study identified the specific enzyme driving this immune suppression and demonstrated that the effect is both reversible and potentially treatable. When researchers blocked the sialoglycan-siglec pathway using sialidase drugs, the tumors shrank and metastasis was prevented in animal models.
"We have uncovered an entirely new checkpoint and, by focusing on it, we can reactivate the immune system and improve our body's innate ability to fight the disease, and even target metastasis," Ryan explained. The research has identified ST6GALNAC6 and Siglec-10 as promising new drug targets for future therapeutic development.
Broader Implications for Cancer Treatment
The breakthrough has implications beyond bowel cancer, potentially benefiting patients with breast and ovarian cancers that share similar tumor microenvironments, as well as those with inflammatory and autoimmune conditions. Dr. Jim Broderick, founder and CEO of Palleon Pharmaceuticals, which collaborated on the research and developed the sialidase drugs used in the study, noted that "targeting sialoglycan biology offers great potential for developing new therapies for diseases characterised by immune dysfunction, including cancer and autoimmunity."
The findings are particularly significant given that immunotherapy has shown limited benefit in bowel cancer compared to its revolutionary impact in melanoma and lung cancer, leaving patients with advanced disease with few treatment options and poor survival outcomes. The research suggests that combining existing immunotherapies with treatments that block sialylation could make these approaches more effective for bowel cancer patients who currently do not respond to immune-boosting therapies.
The study was conducted in collaboration with colorectal surgeons and pathologists at Galway University Hospital, led by Professor Aisling Hogan and Professor Sean Hynes, as well as colorectal cancer experts including Dr. Philip Dunne at Queen's University Belfast.
