Glycan-modified liposomes boost CD4+ and CD8+ T-cell responses by targeting DC-SIGN on dendritic cells

• DOI: 10.1016/j.jconrel.2012.02.007
• Publication Date: 2012-02-15T16:46:49Z
• Authors: Wendy W.J. Unger; Astrid J. van Beelen; Sven C. Bruijns; Medha Joshi; Cynthia M. Fehres; Louis van Bloois; Marleen I. Verstege; Martino Ambrosini; Hakan Kalay; Kamran Nazmi; Jan G. Bolscher; Erik Hooijberg; Tanja D. de Gruijl; Gert Storm; Yvette van Kooyk
• Keywords: CD4-Positive T-Lymphocytes; 570; Antigen Presentation; 610; Mice, Transgenic; Receptors, Cell Surface; Dendritic Cells; CD8-Positive T-Lymphocytes; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Drug Delivery Systems; 0302 clinical medicine; SDG 3 - Good Health and Well-being; Antigens, Neoplasm; Polysaccharides; Liposomes; Animals; Humans; Lectins, C-Type; Cell Adhesion Molecules

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.