Science-translational medicine: targeting sugar molecules to treat cancer

The road is one foot high, and the devil is one foot
high.
Cunning cancer cells use sugar molecules on their surface to stop the body's immune system from attacking
.
Now, researchers at the University of Basel in Switzerland report how to intervene with this mechanism
.

The human immune system is well-equipped to
remove abnormal cells.
Healthy cells have unique characteristics that act as a safety mechanism that allows the immune system to identify them and thus prevent false attacks
.
However, cancer cells secretly manipulate these safety mechanisms so that the immune system also "turns a blind eye"
to them.

Over the past few years, immunotherapy has revolutionized the treatment
of cancer.
These therapies include therapies
that stop cancer cells from suppressing the immune response.
The researchers used synthetic proteins to block so-called "immune checkpoints" that allow immune cells to successfully attack cancer cells
.

"However, for many tumors, the success rate is not high
.
That's why we're looking for new ways to more effectively participate in the anti-tumor immune response," explains
Prof.
Heinz Läubli from the Department of Biomedical Sciences at the University of Basel.

Together with Professor Carolyn Bertozzi of Stanford University, who recently won the Nobel Prize, Professor Heinz Läubli's team reports a promising new approach
.
By altering the sugar molecules on the surface of cancer cells in mice, the researchers were able to significantly enhance
the anti-tumor immune response.
The findings were published in
the journal Science Translational Medicine.

How immune cells turn into traitors

This time, they focused their research on sugar molecules on the surface of cancer cells and cells near cancer cells
.
Healthy cells have special sugars that contain sialic acid on their surface, which are important
for cell-to-cell communication.
However, tumors increase the proportion of these sugars on their surface, a phenomenon known as hypersialylation that is a common feature of
cancer-associated glycosylation.

Macrophages recognize these sialic acid sugars and inadvertently become traitors: they give the impression
that everything is normal to other nearby immune cells.
Experiments conducted by the team in mice showed that targeting this particular type of glycosylation with antibody-sialase conjugates enhanced antitumor immunity and halted tumor progression
.

Target structure of the new therapy

Through further analysis, the researchers found that the main receptor that recognizes sialic acid sugar on mouse macrophages is Siglec-E
.
If the same receptor can be found in the human body, it will be another interesting target for using the patient's own immune system to fight cancer cells
.
They found that hereditary and therapeutic desalivation, as well as the absence of Siglec-E, enhanced the efficacy
of immune checkpoint blockade.

Prof.
Läubli said: "Combining our approach with the immune checkpoint blocking method means that we can really suppress tumor growth
in laboratory mice.
In the next step, the researchers aim to remove sialic acid sugar from tumors and their surroundings in as targeted a way as possible so as not to disrupt the function of healthy cells and eliminate side effects
as much as possible.

Original text search

Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade

SCIENCE TRANSLATIONAL MEDICINE

2 Nov 2022

Vol 14, Issue 669

DOI: 10.
1126/scitranslmed.
abj1270