MPLA incorporation into DC-targeting glycoliposomes favours anti-tumour T cell responses

被引:61
作者
Boks, Martine A. [1 ]
Ambrosini, Martino [1 ]
Bruijns, Sven C. [1 ]
Kalay, Hakan [1 ]
van Bloois, Louis [2 ]
Storm, Gert [2 ,3 ]
Garcia-Vallejo, Juan J. [1 ]
van Kooyk, Yvette [1 ]
机构
[1] Vrije Univ Amsterdam, Med Ctr, Dept Mol Cell Biol & Immunol, Amsterdam, Netherlands
[2] Univ Utrecht, Dept Pharmaceut, Utrecht Inst Pharmaceut Sci, NL-3508 TC Utrecht, Netherlands
[3] Univ Twente, MIRA Inst Biomed Technol & Tech Med, NL-7500 AE Enschede, Netherlands
基金
欧洲研究理事会;
关键词
DC-SIGN; Glycan Lewis(X); Adjuvant MPLA; Liposomes; Antigen targeting; Anti-tumour immunity; HUMAN DENDRITIC CELLS; OLIGOMANNOSE-COATED LIPOSOMES; C-TYPE LECTINS; IN-VIVO; CROSS-PRESENTATION; IMMUNE-RESPONSES; MANNOSE RECEPTOR; ANTIGEN-DELIVERY; SIGN; RECOGNITION;
D O I
10.1016/j.jconrel.2015.06.033
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 Pam(3)CySK(4), 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 gp100(280-288) peptide to CD8(+) T cells compared to nonglycosylated MPLA liposomes. Importantly, antigen cross-presentation of the gp100(280-288) 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. (C) 2015 Elsevier B.V. All rights reserved.
引用
收藏
页码:37 / 46
页数:10
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