Researchers at University of Galway studying cell interactions in bowel cancer have identified innovative strategies to enhance how the body and drug treatments fight the disease.

Colorectal, also known as bowel, cancer is a leading cause of death globally with increasing incidence in developing countries and in younger people.

In Ireland alone, there are more than 2,500 newly diagnosed cases of bowel cancer every year, with limited treatment options for patients at advanced disease stage. 

The findings of the research have been published in life science journal Cell Reports.

Aideen Ryan, Associate Professor in Tumour Immunology at University of Galway’s College of Medicine, Nursing and Health Sciences, said: “Unfortunately, a high proportion of colorectal cancer patients do not respond to immunotherapy. We have identified sugar coated molecules with sialic acid, called sialoglycans, that are present on cells in tumours, known as stromal cells. These are associated with poor responses to immunotherapy. Targeting these molecules enhances the immune response in tumours that have high levels of these cells.”

Approximately 25% of bowel cancer patients have a high density of stromal cells, a type of cancer-supporting cell found in close proximity to cancer cells. 

These patients are the hardest to treat. 

Stromal cells use a number of methods to inhibit or suppress immune cell responses, many of which are utilised by the cancer cells themselves, to promote tumour growth. 

This leads to conventional anti-cancer therapies such as chemotherapy, radiotherapy and, more recently, immunotherapies, having less than favourable results.

The researchers studied a previously unknown mechanism of stromal cell immunosuppression.

It occurs as sugar coated molecules expressed on the stromal cell surface binds to specific protein receptors expressed on the surface of immune T-cells. 

The sugars - sialic acids (or sialoglycans) – bind to receptors called siglecs.

The siglecs stop the cancer killing T cells from working. 

The research showed that stromal cells, when exposed to inflammatory molecules released by bowel cancer cells, express increased amounts of the sialoglycans - on their surface.

It also showed that T cells could be re-activated by using specific drugs to disrupt the binding between the cells.

The researchers tested the findings using stromal cells isolated from bowel cancer patient biopsies and got the same results, confirming that targeting the binding of sialic acid/siglecs may represent an innovative strategy to enhance anti-tumour immunity in immunosuppressive tumour microenvironments.

Dr Ryan added: “Our plan now is to test the effects of combining this new targeting approach with clinically approved immunotherapies in the hope that the combination will improve immune responses to cancer."

“We are fortunate to have access to drugs, called sialidases, that target sialoglycans through our collaborators Palleon Pharmaceuticals to test these new combinations in our laboratory. These sialidase molecules derived from Palleon's EAGLE glyco-immunology drug development platform has recent clinical proof of mechanism.”

Li Peng, chief scientific officer, Palleon, said: “We are delighted to collaborate with Dr Ryan in studying the role of sialoglycans on tumour-associated stromal cells in inhibiting anti-tumour immune responses. Dr Ryan's ground-breaking research highlights the therapeutic potential of targeting stromal cell sialoglycans in the tumour microenvironment as a cancer treatment approach, utilising a sialidase molecule derived from Palleon's EAGLE glyco-immunology drug development platform that has clinical proof of mechanism."

Article: Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumour microenvironment

Source: University of Galway