Antibodies Unmask Pancreatic Tumors Hiding in Sugar-Coated Disguise

Stories of wolves disguising themselves as Little Red Riding Hood’s grandmother—or predators hiding in sheep’s clothing—are reminders of how deception can mask danger. Cancer, too, can be a master of disguise, slipping past the body’s defenses undetected. Among them, pancreatic cancer is especially notorious for its stealth, often remaining hidden until it’s far too late.

This motivated immunologist and glycobiologist Mohamed Abdel-Mohsen from Northwestern University to investigate pancreatic tumors’ evasion tactics, particularly looking at their use of complex sugars, or glycans, which have been found to regulate the immune system.¹

Indeed, the team found that pancreatic tumors do cloak themselves with glycoproteins, normally found on healthy cells, which signal immune cells not to eat them. In their findings, published in Cancer Research, the researchers developed an antibody to block the tumor glycoprotein–immune cell receptor binding, exposing tumor cells to macrophage attack.² These findings may guide the development of an antibody therapy for pancreatic ductal adenocarcinoma (PDAC) and beyond if other diseases follow a similar pattern of immune evasion.

The researchers focused on sialic acid-binding Ig-like lectin (Siglec) receptors, which are primarily found on immune cells and act as immune checkpoints to discriminate between ‘self’ and ‘non-self’ cells. These receptors bind to sialic acid; a sugar molecule found on the surface of healthy cells.

Using single-cell RNA sequencing data from human PDAC tumors, the researchers identified Siglec-10 as being predominantly expressed on multiple immune cells within the tumor microenvironment. This suggested that Siglec-10 may contribute to the cancer’s successful evasion of the immune system.

The researchers sought to identify the ligand of Siglec-10 on PDAC tumors. They discovered that this receptor bound to cluster of differentiation 24 (CD24)—a sialic acid–coated glycoprotein known to interact with Siglec-10 in breast and ovarian cancer cells.³ Additionally, Siglec-10 primarily bound to the subunits of integrin α3β1, integrin alpha-3 (ITGA3) and integrin beta-1 (ITGB1), on PDAC cells.

Not only did immune cells expressing Siglec-10 bind to these sugars, but increased sugar expression on PDAC cells also correlated with more aggressive disease features and a worse survival prognosis.

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Then, the team tested whether ITGA3 and ITGB1 helped PDAC cells evade macrophage-mediated phagocytosis. Indeed, cells that did not express these sugars were more susceptible to be gobbled up by macrophages, while sugar-coated cells evaded detection.

Having found this hiding mechanism, the researchers screened thousands of hybridomas, immortalized B cells that produce antibodies, before they identified an antibody that blocked Siglec-10 interactions. Because Siglec-10 can bind to multiple ligands, they proposed to use antibodies that bind to Siglec-10 directly to prevent anything else from binding to the receptor. The team tested the anti-Siglec-10 antibody in mice xenografted with human PDAC cells. This treatment successfully blocked the interaction, reactivating immune cells like macrophages, and slowed tumor growth.

Excited by these findings, Abdel-Mohsen and his team are refining this antibody for human use, moving towards safety and dosing trials. In parallel, the researchers are testing it in combination with chemotherapy and immunotherapy, to better inform which therapy might work best for certain people.

Beyond pancreatic cancer, “We’re now asking whether the same sugar-coat trick shows up in other hard-to-treat cancers, such as glioblastoma, and in non-cancer diseases where the immune system is misled,” said Abdel-Mohsen in a statement.