Glycoengineering provides insight into new cancer immunotherapies

Posted: January 24, 2023

By remodelling sugars on cell surfaces, GlycoNet researchers aim to map the linkages between proteins in the immune system and sugars on cancer cells

Dr. Chantelle Capicciotti is a GlycoNet esearcher at Queen's University.

GlycoNet researchers Dr. Chantelle Capicciotti from Queen’s University and Dr. Matthew Macauley from the University of Alberta are developing technologies to study cancer cells and understand how they evade the immune system.

Normally, the immune system tells abnormal cells apart from healthy ones by the different features on the cells. For example, healthy cells usually display sialic acids, which are a type of sugar, on their cell surfaces. When a family of proteins from the immune system called Siglecs scans these cells, they first bind to sialic acids. The binding triggers a signal telling the body that the encountered cell is safe, helping the immune system distinguish “self” from “non-self.” However, cancer cells can trick the immune system by boosting the proportion of sialic acids on their cell surface. When Siglecs meet a cancer cell, a binding interaction occurs, leaving the false impression to the immune system that the cancer cell is safe. The immune system does not attack these cancer cells.

It has been reported that Siglecs are one of the mechanisms cancer cells leverage to evade the immune system, but according to Capicciotti, there is limited understanding of the structures and the identities of biomolecules that Siglecs interact with.

“This is important for developing cancer therapeutics,” says Capicciotti, “if we know what is binding to Siglecs, we can block the binding interactions, and the immune system will be able to identify cancer cells and destroy them.”

The problem is that there are 15 known Siglecs in humans and a variety of sialic acid-containing sugars as well as sialylated glycoproteins on cell surfaces. Each Siglec binds to different sialic acids and promotes immune responses through distinct mechanisms. Many of these mechanisms and binding interactions are not well-known. To find out which Siglec binds to which type of sialic acid-containing sugars on cell surfaces, Capicciotti and Macauley have joined efforts with Lance Wells and Peng Zhao from the Complex Carbohydrates Research Centre at the University of Georgia, as the teams have complementary tools to solve this puzzle.

In 2020, the Macauley Lab reported the development of a platform that used Velcro-like effects to strengthen the sugar-binding properties of Siglecs, making them easier to study.

In the Capicciotti Lab, researchers have been focusing on glycan editing, where they use enzymes to chew up or install sugar derivatives or glycans on cell surfaces. Traditionally, cell surface remodelling is done by removing the genes that correspond to the enzymes responsible for installing or fragmenting glycans on cell surfaces. However, this method can take weeks, is not always versatile, and requires a comprehensive platform. “By using enzymes to modify cells from the outside, we can remodel the cells within a few hours,” says Capicciotti.

For this project, Capicciotti uses the enzymes to selectively install analogues of sialic acids developed from her lab. These analogues have a small chemical functionality that makes them “activatable” by UV light. When the analogue is in proximity with its Siglec binding partner, the UV irradiation cross-links the two molecules. This means they are now linked together chemically and will not fall apart, making the binding interactions easier to detect and isolate. If, however, the Siglec of interest is not the right binding partner of the selectively installed analogue, no cross-linking will occur upon UV irradiation. In this case, the two molecules do not chemically link together, and the researchers can infer that this pair of Siglec and sialic acids likely are not what cancer cells leverage to evade the immune system.

The Capicciotti and Macauley Labs have demonstrated a proof of concept with a panel of enzymes capable of installing UV-activatable sialic acids on cell surfaces that can cross-link with well-studied Siglecs.

“Right now, we’re exploring Siglecs that are less known and less studied,” says Capicciotti. “Our next step is to collaborate with proteomics experts at the Complex Carbohydrates Research Centre to uncover which glycoproteins are displaying the sialic acids we installed on the cell surfaces that were involved with binding to the Siglec.”

The team’s final goal is to identify targets involved in binding between Siglecs and sialylated glycoproteins on cancer cells. This can facilitate the development of new inhibitors to block off these binding interactions so that the immune system can recognize cancer cells and trigger appropriate immune responses.

This project is funded by GlycoNet, the Complex Carbohydrates Research Centre, Queen’s University and Alzheimer Society of Canada.

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