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

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• 作者：Wendy W.J. Unger^a ; ¹ ; ^{w.unger@vumc.nl} ; Astrid J. van Beelen^a ; ¹ ; Sven C. Bruijns^a ; Medha Joshi^d ; ² ; Cynthia M. Fehres^a ; Louis van Bloois^d ; Marleen I. Verstege^a ; Martino Ambrosini^a ; Hakan Kalay^a ; Kamran Nazmi^e ; Jan G. Bolscher^e ; Erik Hooijberg^b ; Tanja D. de Gruijl^c ; Gert Storm^d ; Yvette van Kooyk^a
• 关键词：DC-SIGN ; Antigen-targeting ; Glycans ; Anti-tumor immunity ; CD4 T-cells ; CD8 T-cells
• 刊名：Journal of Controlled Release
• 出版年：2012
• 期刊代码：25_01683659
• 类别：pha
• 出版时间：30 May, 2012
• 卷：160
• 期：1
• 页码：88-95
• 文件大小：611 K

摘要

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-纬-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.