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- Title
Glycan modification of glioblastoma-derived extracellular vesicles enhances receptor-mediated targeting of dendritic cells.
- Authors
Dusoswa, Sophie A.; Horrevorts, Sophie K.; Ambrosini, Martino; Kalay, Hakan; Paauw, Nanne J.; Nieuwland, Rienk; Pegtel, Michiel D.; Würdinger, Tom; Van Kooyk, Yvette; Garcia-Vallejo, Juan J.
- Abstract
Glioblastoma is the most prevalent and aggressive primary brain tumour for which total tumour lysate-pulsed dendritic cell vaccination is currently under clinical evaluation. Glioblastoma extracellular vesicles (EVs) may represent an enriched cell-free source of tumour-associated (neo-) antigens to pulse dendritic cells (DCs) for the initiation of an anti-tumour immune response. Capture and uptake of EVs by DCs could occur in a receptor-mediated and presumably glycan-dependent way, yet the glycan composition of glioblastoma EVs is unknown. Here, we set out to characterize the glycocalyx composition of glioblastoma EVs by lectin-binding ELISA and comprehensive immunogold transmission electron microscopy (immuno-TEM). The surface glycan profile of human glioblastoma cell line-derived EVs (50–200 nm) was dominated by α-2,3- and α-2,6 linked sialic acid-capped complex N-glycans and bi-antennary N-glycans. Since sialic acids can trigger immune inhibitory sialic acid–binding Ig-like lectin (Siglec) receptors, we screened for Siglec ligands on the EVs. Glioblastoma EVs showed significant binding to Siglec-9, which is highly expressed on DCs. Surprisingly, however, glioblastoma EVs lack glycans that could bind Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN, CD209), a receptor that mediates uptake and induction of CD4+ and CD8+ T cell activation. Therefore, we explored whether modification of the EV glycan surface could reduce immune inhibitory Siglec binding, while enhancing EV internalization by DCs in a DC-SIGN dependent manner. Desialylation with a pan-sialic acid hydrolase led to reduction of sialic acid expression on EVs. Moreover, insertion of a high-affinity ligand (LewisY) for DC-SIGN resulted in a four-fold increase of uptake by monocyte-derived DCs. In conclusion, we show that the glycocalyx composition of EVs is a key factor of efficient DC targeting and that modification of the EV glycocalyx potentiates EVs as anti-cancer vaccine.
- Subjects
DENDRITIC cells; GLIOBLASTOMA multiforme; FOLLICULAR dendritic cells; CELL adhesion; SIALIC acids; TRANSMISSION electron microscopy; GLYCOCALYX
- Publication
Journal of Extracellular Vesicles, 2019, Vol 8, Issue 1, p1
- ISSN
2001-3078
- Publication type
Article
- DOI
10.1080/20013078.2019.1648995