title: MPLA incorporation into DC-targeting glycoliposomes favours anti-tumour T cell responses.
abstract: Dendritic cells (DC) are attractive targets for cancer immunotherapy as they initiate strong and long-lived tumour-specific T cell responses. DC can be effectively targeted in vivo with tumour antigens by using nanocarriers such as liposomes. Cross-presentation of tumour antigens is enhanced with strong adjuvants such as TLR ligands. However, often these adjuvants have off-target effects, and would benefit from a DC-specific targeting strategy, similar to the tumour antigen. The goal of this study was to develop a strategy for specifically targeting DC with tumour antigen and adjuvant by using glycoliposomes. We have generated liposomes containing the glycan Lewis(Le)(X) which is highly specific for the C-type lectin receptor DC-SIGN expressed by DC. Le(X)-modified liposomes were taken up by human monocyte-derived DC in a DC-SIGN-specific manner. As adjuvants we incorporated the TLR ligands Pam3CySK4, Poly I:C, MPLA and R848 into liposomes and compared their adjuvant capacity on DC. Incorporation of the TLR4 ligand MPLA into glycoliposomes induced DC maturation and production of pro-inflammatory cytokines, in a DC-SIGN-specific manner, and DC activation was comparable to administration of soluble MPLA. Incorporation of MPLA into glycoliposomes significantly enhanced antigen cross-presentation of the melanoma tumour antigen gp100280-288 peptide to CD8(+) T cells compared to non-glycosylated MPLA liposomes. Importantly, antigen cross-presentation of the gp100280-288 peptide was significantly higher using MPLA glycoliposomes compared to the co-administration of soluble MPLA with glycoliposomes. Taken together, our data demonstrates that specific targeting of a gp100 tumour antigen and the adjuvant MPLA to DC-SIGN-expressing DC enhances the uptake of peptide-containing liposomes, the activation of DC, and induces tumour antigen-specific CD8(+) T cell responses. These data demonstrate that adjuvant-containing glycoliposome-based vaccines targeting DC-SIGN(+) DC represent a powerful new approach for CD8(+) T cell activation.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
authors.forename: Martine A
authors.initials: MA
authors.lastname: Boks
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
authors.forename: Martino
authors.initials: M
authors.lastname: Ambrosini
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
authors.forename: Sven C
authors.initials: SC
authors.lastname: Bruijns
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
authors.forename: Hakan
authors.initials: H
authors.lastname: Kalay
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: van Bloois
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands; MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center (VUmc), Amsterdam, The Netherlands.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Garcia-Vallejo
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center (VUmc), Amsterdam, The Netherlands. Electronic address: y.vankooyk@vumc.nl.
authors.forename: Yvette
authors.initials: Y
authors.lastname: van Kooyk
mesh_terms: D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D017951:Antigen Presentation / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects*; D016503:Drug Delivery Systems; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects; D008546:Melanoma, Experimental / Q000235:genetics; D021141:Nucleic Acid Amplification Techniques / Q000379:methods*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000187:drug effects; D058951:gp100 Melanoma Antigen / Q000187:drug effects
chemical_list: D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D016207:Cytokines; D008081:Liposomes; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D058951:gp100 Melanoma Antigen
keywords: Adjuvant MPLA; Anti-tumour immunity; Antigen targeting; DC-SIGN; Glycan Lewis(X); Liposomes