Researchers at the University of Galway have revealed the results of a world-first study into how bowel cancer shuts down the immune system, and how this can be reversed to improve treatment.
The findings have been published in the Journal for ImmunoTherapy of Cancer (JITC).
The research team showed how structural stromal cells switch off the immune system and how the body’s own killer cells can be switched back on, opening up the opportunity for a completely new approach to optimising immunotherapy for patients.
Colorectal cancer – commonly referred to as bowel cancer – is one of the world’s most common cancers and the second leading cause of cancer death worldwide.
Diagnoses in people under 50 have been climbing in recent decades, with recent global analysis showing these early-onset cases have almost doubled since 1990. In Ireland, the disease affects more than 2,500 people a year.
Professor Aideen Ryan, Professor in Tumour Immunology at University of Galway, said, “While immunotherapy has revolutionised care in cancers such as melanoma and lung cancer, it has shown very limited benefit in bowel cancer, leaving patients with advanced disease with few treatment options and poor survival outcomes.”
The breakthrough research discovery is the first to demonstrate that tumour stromal cells – the structural cells that support cancer growth – are directly reprogramming the immune system.
They do this by switching off, or hijacking, two of our body’s most important tumour-fighting cells – the natural killers (NK) and macrophages – rendering them unable to attack the cancer.
Professor Ryan said, “The interaction between the cancer, our body’s healthy cells and our defence mechanism is a complex one, but our research shows that the cancer is essentially creating an immune brake – it is blocking the body’s natural response and fight mechanism.”
Tumour stromal cells are the structural cells which allow the cancer to grow. They are coated in sugars called sialoglycans. These interact with receptors on the body’s immune cells called Siglecs.
This interaction causes the body’s natural defence response to be switched off and unresponsive when immunotherapy is used, and therefore unable to attack the cancer.
The research identified a specific enzyme that drives this process of ‘switching off’, as it produces the Siglec-binding sugars on stromal cells.
When the researchers blocked this pathway using drugs called sialidases, they could show that the body’s most important tumour-fighting cells – the natural killers (NK) and macrophages – reactivated. It showed that the tumours shrank and the spread of cancer, known as metastasis, was prevented.
The multidisciplinary research was conducted in collaboration with colorectal surgeons and pathologists at Galway University Hospital, led by Professor Aisling Hogan and Professor Sean Hynes.
It also involved experts in colorectal cancer – Dr Philip Dunne, Queen’s University Belfast and experts in targeting sialoglycans at Palleon Pharmaceuticals, MA, USA, who have developed sialidase drugs that disrupt the sialoglycan-Siglec interaction.
Professor Ryan added, “Our research is a clear breakthrough in our understanding of bowel cancer and how immunotherapy could be more successful.”
“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.”
“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.”
Michael O’Dwyer, Professor of Medicine and Scientific Director of University of Galway Cancer Centre, said, “The work of Professor Ryan and her research team highlights an important interplay between cells within a tumour, facilitating disease progression and metastasis.”
“This is an excellent example of impactful, innovative research with strong industry engagement currently being undertaken within the University of Galway Cancer Centre.”
Jim Broderick, M.D., Chief Executive Officer and Founder of Palleon Pharmaceuticals, said, “The sialoglycan-Siglec axis of immunosuppression in cancer was underappreciated until very recently.”
“Targeting sialoglycan biology offers great potential for developing new therapies for diseases characterized by immune dysfunction, including cancer and autoimmunity.”
“The discoveries from Professor Ryan’s lab bring new hope to patients battling colorectal cancer and other malignancies that have proven resistant to existing immunotherapies.”
Professor Ryan’s pioneering cancer research is featured in the Breakthrough Cancer Research exhibition, Cancer Revolution: Science, Innovation and Hope, which is on display in Stephen’s Green Shopping Centre until Friday, October 31.
It includes striking microscopy images of stromal cells interacting with tumours and a 3D tumour model, helping to visualise how these cells shut down the immune system in bowel cancer.
The display explains how Professor Ryan’s team discovered that stromal cells act as an “immune brake” and how targeting this brake could finally allow immunotherapy to work for patients with colorectal cancer.
