July 23, 2024

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Targeting Sugar Molecules in Sugar-Immune Therapy

Targeting Sugar Molecules in Sugar-Immune Therapy Shows Enhanced Anti-Tumor Efficacy



Targeting Sugar Molecules in Sugar-Immune Therapy Shows Enhanced Anti-Tumor Efficacy.

It is well-known that the immune system serves as the body’s defense network, equipped with various abilities to eliminate abnormal cells.

As a safety mechanism, healthy cells typically carry labels recognizable by the immune system to prevent mistaken attacks.

However, when cancer cells manipulate this mechanism, the defense network may become compromised.

Over the past decade, immunotherapy has revolutionized cancer treatment.

Immune checkpoint blockade (ICB) therapies, including antibodies that block cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death receptor-1 (PD-(L)1), have significantly improved the prognosis of cancer patients.

However, success rates remain low, with the majority of patients showing no response to these immunotherapies.

Therefore, the search for new strategies to engage the anti-tumor immune response more effectively and expand the pool of beneficiaries is essential.

 

To seek a breakthrough, some scientists have turned their attention to sugar molecules on the surface of cancer cells. Sialic acid is a specific polysaccharide that can be recognized by a series of surface proteins, primarily found on innate immune cells and activated T cells within tumor sites.

Recently, a new study published in “Science Translational Medicine,” conducted by Professor Heinz Läubli and his team from the University of Basel’s Department of Biomedicine, in collaboration with 2022 Nobel Prize laureate in Chemistry, Professor Carolyn Bertozzi from Stanford University, provides mechanistic evidence for tumor sialylation-mediated immune suppression.

It demonstrates the effectiveness and feasibility of therapeutic desialylation in anti-tumor therapy, highlighting its potential in combination with classical immune checkpoint inhibitors.

Targeting Sugar Molecules in Sugar-Immune Therapy Shows Enhanced Anti-Tumor Efficacy

 

 

In the tumor microenvironment, tumor sialylation contributes to establishing an immune-suppressive environment by inhibiting the anti-tumor immune response through engagement with immunoregulatory immunoglobulin-like lectins (Siglecs) expressed on tumor-infiltrating immune cells. Recent research suggests that the sialic acid polysaccharide-Siglec axis serves as a novel immune checkpoint, offering a target to drive both innate and adaptive anti-tumor immunity. However, due to the presence of multiple Siglecs and their widespread expression patterns within the immune system, the exact mechanisms remain unclear.

The team had previously identified Siglec-9 as an inhibitory receptor expressed on tumor-infiltrating T cells in various cancers, suggesting that tumor cell desialylation could impede tumor growth and enhance anti-tumor immunity in mouse models. Treatment with sialidase also yielded similar results. However, the feasibility of this enhanced immune checkpoint blockade therapy remained to be proven.

In this new study, researchers initially analyzed data from The Cancer Genome Atlas (TCGA) database containing information on solid tumors, revealing a correlation between the expression of sialic acid polysaccharide genes and immune gene expression. Tumor sialylation was associated with distinct immune states in human cancers and reduced survival rates.

 

Targeting Sugar Molecules in Sugar-Immune Therapy Shows Enhanced Anti-Tumor Efficacy

 

 

Subsequently, the researchers conducted a more detailed investigation of sialic acid-mediated immune suppression in different mouse tumor models. They used an antibody-sialidase conjugate (rituximab-sialidase) to selectively remove Siglec ligands from the tumor microenvironment, boosting anti-tumor immunity and halting tumor progression.

Single-cell RNA sequencing showed that tumor desialylation polarized macrophages in both mouse and human tumors. Siglec-E was identified as the primary receptor highly sialylated on macrophage surfaces.

Finally, the researchers found that genetic and therapeutic desialylation, as well as the loss of Siglec-E, enhanced the efficacy of immune checkpoint inhibitors. Therefore, therapeutic desialylation emerges as an immunotherapy approach that reshapes macrophage phenotypes and enhances adaptive anti-tumor immune responses.

In conclusion, these findings provide compelling evidence for further clinical development of sialic acid polysaccharide-Siglec targeting agents, particularly in combination with PD-1 and CTLA-4 immune checkpoint blockade therapies.

Paper Link

 

 

 

Targeting Sugar Molecules in Sugar-Immune Therapy Shows Enhanced Anti-Tumor Efficacy

(source:internet, reference only)


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