Glycan-modified liposomes boost CD4+ and CD8+ T-cell responses by targeting DC-SIGN on dendritic cells
Glycan-modified liposomes boost CD4+ and CD8+ T-cell responses by targeting DC-SIGN on dendritic cells
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DOI：
10.1016/j.jconrel.2012.02.007
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发表时间：
2012-05-30
影响因子：
10.8
通讯作者：
van Kooyk, Yvette
中科院分区：
文献类型：
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作者：
Unger, Wendy W. J.;van Beelen, Astrid J.;van Kooyk, Yvette
癌症免疫治疗需要由树突状细胞 (DC) 发起的有效的肿瘤特异性 CD8+ 和 CD4(+) T 细胞反应。通过利用 C 型凝集素受体 (CLR) 的表达，肿瘤抗原可以在体内特异性靶向 DC，C 型凝集素受体 (CLR) 与抗原上的碳水化合物结构结合，导致内化并将抗原呈递给 T 细胞。我们探索了聚糖修饰的脂质体将抗原靶向树突状细胞以增强小鼠和人类 T 细胞反应的潜力。由于 DC-SIGN 是 DC 上表达的 CLR，因此用 DC-SIGN 结合聚糖 Lewis (Le)(B) 或 Le(X) 修饰脂质体。脂质体的聚糖修饰导致表达人 DC-SIGN 的 BMDC 的结合和内化增加。在 LPS 存在的情况下，与未修饰的脂质体或可溶性抗原相比，封装的抗原向 CD4(+) 和 CD8(+) T 细胞的呈递效率提高了 100 倍。类似地，在LPS存在的情况下，将人moDC与黑色素瘤抗原MART-1封装的LeX包被的脂质体一起温育，导致对MART-1特异性CD8(+) T细胞克隆的抗原呈递增强。此外，该制剂可驱动原代CD8+T细胞分化为大量四聚体特异性、产生IFN-γ的效应T细胞。总之，我们的数据证明了基于糖脂质体的疫苗针对 DC-SIGN 激活 CD4(+) 和 CD8(+) 效应 T 细胞的效力。这种方法可能为癌症患者的治疗提供改进的选择，并为原位 DC 靶向疫苗接种开辟道路。 (C) 2012 Elsevier B.V. 保留所有权利。
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 humanmoDCwithmelanoma antigen MART-1-encapsulated liposomes coated with LeX 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-gamma-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. (C) 2012 Elsevier B. V. All rights reserved.