Abstract
Many tumors display alterations in the biosynthetic pathways of glycosylation, resulting in increased expression of specific tumor-associated glycan structures. Expression of these altered glycan structures is associated with metastasis and poor prognosis. Antigen presenting cells can recognize tumor-associated glycan structures, including the truncated O-glycan Tn antigen, via specific glycan receptors. Tn antigen-mediated activation of the C-type lectin MGL on dendritic cells induces regulatory T cells via the enhanced secretion of IL-10. Although these findings indicate that MGL engagement by glycan ligands can modulate immune responses, the impact of MGL ligation on dendritic cells is still not completely understood. Therefore, we employed RNA sequencing, GO term enrichment and pathway analysis on human monocyte-derived dendritic cells stimulated with two different MGL glycan ligands. Our analyses revealed a reduced expression of genes coding for key enzymes involved in the glycolysis pathway, TCA cycle, and oxidative phosphorylation. In concordance with this, extracellular flux analysis confirmed the decrease in glycolytic activity upon MGL triggering in human dendritic cells. To our knowledge, we are the first to report a diminished glycolytic activity of human dendritic cells upon C-type lectin stimulation. Overall, our findings highlight the impact of tumor-associated glycans on dendritic cell biology and metabolism and will increase our understanding on how glycans can shape immunity.
Highlights
Expression of tumor-associated glycan structures has emerged as one of the hallmarks of cancer, and is associated with many of the pathological steps in tumor progression [1]
The macrophage galactose-type lectin receptor (MGL, CD301) has a high preference for tumor-associated glycans and can recognize terminal N-acetylgalactosamine (α- or β-linked GalNAc) residues, as found for instance in the truncated O-glycan Tn antigen, which is predominantly expressed on many cancer cells, including, colorectal, cervical and breast cancer cells, and has been associated with metastasis and poor prognosis [2,3,4,5]
Vicia villosa lectin (VVL) bound both glycodendrimers with the same affinity, confirming equal coating of both glycodendrimers, whereas Helix pomatia agglutinin (HPA) binding to the αGalNAc glycodendrimers was stronger compared to the GalNAcβ1-4Gal glycodendrimers (Figure 1A)
Summary
Expression of tumor-associated glycan structures has emerged as one of the hallmarks of cancer, and is associated with many of the pathological steps in tumor progression [1]. MGL levels are increased on tumor-associated DCs and Mφs, as well as on tolerogenic DCs [5, 12, 14], which are able to dampen T cell immunity in a MGLdependent manner through the interaction with Tn antigen on CD45 molecules of activated effector T cells. This results in decreased T cell proliferation, reduced inflammatory cytokine production and increased T cell apoptosis [15]. These findings highlight the potential of MGL to modulate immune responses, the impact of MGL-glycan interactions on DC function is still not completely understood
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