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

Abstract Cancer immunotherapyrequires potent tumor-specific CD8 + and CD4 + T-cell responses, initiated by dendritic cells (DCs). Tumor antigenscan be specifically targeted to DCs in vivo by exploiting their expression of C-type lectinreceptors (CLR), which bind carbohydrate structures on antigens, resulting in internalization and antigen presentationto 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-SIGNis a CLR expressed on DCs, liposomes were modified with DC-SIGN-binding glycansLewis (Le) B or Le X . Glycanmodification 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-presentationto 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-SIGNfor 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.