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

• Published in: Journal of controlled release Vol. 216; pp. 37 - 46
• Main Authors: Boks, Martine A., Ambrosini, Martino, Bruijns, Sven C., Kalay, Hakan, van Bloois, Louis, Storm, Gert, Garcia-Vallejo, Juan J., van Kooyk, Yvette
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.10.2015
• Subjects: Adjuvant MPLA; Anti-tumour immunity; Antibodies, Neoplasm - biosynthesis; Antibodies, Neoplasm - genetics; Antigen Presentation - drug effects; Antigen targeting; Antigens, Neoplasm - chemistry; CD8-Positive T-Lymphocytes - drug effects; Cytokines - biosynthesis; DC-SIGN; Dendritic Cells - drug effects; Drug Delivery Systems; Glycan LewisX; gp100 Melanoma Antigen - drug effects; Humans; Liposomes; Liposomes - chemistry; Macrophages - drug effects; Melanoma, Experimental - genetics; Nucleic Acid Amplification Techniques - methods; T-Lymphocytes, Cytotoxic - drug effects; Toll-Like Receptor 4 - drug effects; Glycan LewisX; Anti-tumour immunity; Antigen targeting; Liposomes; DC-SIGN; Adjuvant MPLA; Glycan Lewis(X)
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2015.06.033

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. LeX-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. [Display omitted]