Novel approaches to activating the immune system in colorectal cancer

Nial O’Reilly

Nial was awarded an Attracta O’Regan – Cancer Research – Musgrave PhD Scholarship in partnership with Breakthrough Cancer Research, under the supervision of Dr. Aideen Ryan at University of Galway.

Metastatic Colorectal cancer (CRC) is one of the deadliest forms of cancer, accounting for 12.4% of annual deaths and increasing year by year. State of the art anti-cancer treatments (immunotherapies) are still ineffective at treating this cancer. The microenvironment where the tumours are formed is still very resistant to these therapies. A subtype of CRC named Consensus molecular subtype 4 (CMS4) has the poorest response to immunotherapies and is characterized by a high number of connective tissue cells termed stromal cells.

Sialic acid is a common component of glycan molecules and can alter protein function. This would occur through overexpression of Sialyltranferases (STs), the enzymes that accelerate the attachment of sialic acids to the glycan molecule. Sialic acid-containing molecules are recognized by unique proteins with Silaic acid receptors (Siglecs) found on the surfaces of immune cells. Dr Ryan’s group has discovered that the binding of sialic acids to stromal cells can suppress T cell function in CRC.

In this PhD, I propose to extend these findings to understand the specific signaling mechanisms in CRC surface level cells that enable CRC to resist immunotherapies. This research will be broken down into 3 primary objectives. Firstly, identify the Siglec-ligand interactions that are the most abundant in the CRC tumour microenvironment (TME). Next, identify the signaling molecules in CRC outer layer cells that are responsible for establishing these interactions. Finally, target these siglec-ligand interactions to reverse the CRC resistance in the TME and sensitize CRC cells to treatments like immunotherapy.