A research team from MIT and Stanford University has developed a new technique designed to push the immune system to go after tumor cells. The strategy is aimed at helping cancer immunotherapy succeed in far more patients than it does today.

At the center of the work is a way to undo a built in "brake" that tumors can trigger to keep immune cells from attacking. That brake is tied to sugars called glycans, which sit on the surface of cancer cells.

The scientists found that blocking these glycans with proteins known as lectins can greatly strengthen immune activity against cancer cells. To do this in a targeted way, they built multifunctional molecules called AbLecs that pair a lectin with an antibody that homes in on tumors.

"We created a new kind of protein therapeutic that can block glycan-based immune checkpoints and boost anti-cancer immune responses," says Jessica Stark, the Underwood-Prescott Career Development Professor in the departments of Biological Engineering and Chemical Engineering. "Because glycans are known to restrain the immune response to cancer in multiple tumor types, we suspect our molecules could offer new and potentially more effective treatment options for many cancer patients."

Stark, who is also a member of MIT's Koch Institute for Integrative Cancer Research, led the study as the paper's lead author. Carolyn Bertozzi, a Stanford professor of chemistry and director of the Sarafan ChEM Institute, served as the senior author. The findings were published in Nature Biotechnology.

How Cancer Uses Immune Brakes

One of the biggest goals in cancer treatment is teaching the immune system to spot tumor cells and eliminate them. A major group of immunotherapy drugs called checkpoint inhibitors works by interrupting the interaction between two proteins, PD-1 and PD-L1. By blocking that connection, these medicines remove a brake that tumors use to keep immune cells such as T cells from killing cancer cells.

Checkpoint inhibitors that target the PD-1 PD-L1 pathway are already approved for several cancers. For some people, they can produce long lasting remission. For many others, however, they provide little benefit or none at all.

Because of that gap, researchers are searching for other ways tumors suppress the immune system. One promising target involves interactions between tumor glycans and receptors on immune cells.

Siglecs, Sialic Acid, and a Sugar Based Checkpoint

Glycans appear on nearly all living cells, but cancer cells often carry versions not found on healthy cells. Many of these tumor specific glycans include a sugar building block called sialic acid. When sialic acids attach to lectin receptors on immune cells, they can switch on an immune dampening pathway. The lectins that recognize sialic acid are called Siglecs.

"When Siglecs on immune cells bind to sialic acids on cancer cells, it puts the brakes on the immune response. It prevents that immune cell from becoming activated to attack and destroy the cancer cell, just like what happens when PD-1 binds to PD-L1," Stark says.