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

作者：Boks Martine A; Ambrosini Martino; Bruijns Sven C; Kalay Hakan; van Bloois Louis; Storm Gert; Garcia Vallejo Juan J; van Kooyk Yvette^*

来源：Journal of Controlled Release, 2015, 216: 37-46.

DOI：10.1016/j.jconrel.2015.06.033

• DC-SIGN
• Glycan Lewis(X)
• Adjuvant MPLA
• Liposomes
• Antigen targeting
• Anti-tumour immunity

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.

• 出版日期2015-10-28