title: Glycan-modified liposomes boost CD4+ and CD8+ T-cell responses by targeting DC-SIGN on dendritic cells.
abstract: Cancer immunotherapy requires potent tumor-specific CD8(+) and CD4(+) T-cell responses, initiated by dendritic cells (DCs). Tumor antigens can be specifically targeted to DCs in vivo by exploiting their expression of C-type lectin receptors (CLR), which bind carbohydrate structures on antigens, resulting in internalization and antigen presentation to T-cells. We explored the potential of glycan-modified liposomes to target antigens to DCs to boost murine and human T-cell responses. Since DC-SIGN is a CLR expressed on DCs, liposomes were modified with DC-SIGN-binding glycans Lewis (Le)(B) or Le(X). Glycan modification of liposomes resulted in increased binding and internalization by BMDCs expressing human DC-SIGN. In the presence of LPS, this led to 100-fold more efficient presentation of the encapsulated antigens to CD4(+) and CD8(+) T-cells compared to unmodified liposomes or soluble antigen. Similarly, incubation of human moDC with melanoma antigen MART-1-encapsulated liposomes coated with Le(X) in the presence of LPS led to enhanced antigen-presentation to MART-1-specific CD8(+) T-cell clones. Moreover, this formulation drove primary CD8(+) T-cells to differentiate into high numbers of tetramer-specific, IFN-γ-producing effector T-cells. Together, our data demonstrate the potency of a glycoliposome-based vaccine targeting DC-SIGN for CD4(+) and CD8(+) effector T-cell activation. This approach may offer improved options for treatment of cancer patients and opens the way to in situ DC-targeted vaccination.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. w.unger@vumc.nl
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: Unger
authors.forename: Astrid J
authors.initials: AJ
authors.lastname: van Beelen
authors.forename: Sven C
authors.initials: SC
authors.lastname: Bruijns
authors.forename: Medha
authors.initials: M
authors.lastname: Joshi
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Fehres
authors.forename: Louis
authors.initials: L
authors.lastname: van Bloois
authors.forename: Marleen I
authors.initials: MI
authors.lastname: Verstege
authors.forename: Martino
authors.initials: M
authors.lastname: Ambrosini
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.forename: Kamran
authors.initials: K
authors.lastname: Nazmi
authors.forename: Jan G
authors.initials: JG
authors.lastname: Bolscher
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011134:Polysaccharides / Q000008:administration & dosage / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D008081:Liposomes; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin