Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development
Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development
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DOI：
10.1016/j.jconrel.2017.01.004
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发表时间：
2017-02-10
影响因子：
10.8
通讯作者：
Gursel, Ihsan
中科院分区：
文献类型：
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作者：
Bayyurt, Banu;Tincer, Gizem;Gursel, Ihsan
基于核酸的Toll样受体（TLR）配体是有前途的佐剂和免疫抑制剂。TLR配体的组合通过触发不同的信号传导途径提供协同免疫活性来增强免疫应答，并且可以影响抗原依赖性T细胞免疫记忆。然而，由于核酸酶攻击，它们的短循环时间阻碍了它们的临床性能。脂质体以高包封效率和载药量提供基于蛋白质和核酸的药物的包合。此外，它们保护货物免受酶切割，同时提供稳定性并增强生物活性。在此，我们的目的是开发一种脂质体载体系统共封装TLR 3（聚肌苷酸-聚胞苷酸;聚（I：C））和TLR 9（表达非甲基化CpG基序的寡脱氧核苷酸（ODN）; CpG ODN）配体作为免疫佐剂与蛋白抗原一起。为了证明这种储库系统不仅诱导协同先天免疫激活，而且还增强抗原依赖性免疫应答，我们分析了双配体包封的脂质体在长期癌症保护测定中的效力。数据显示，CpG ODN和poly（I：C）共包封显着增强了脾细胞的细胞因子产生。在与共包封CpG ODN和poly（I：C）的脂质体孵育后，树突状细胞的活化和成熟以及巨噬细胞的杀菌能力沿着配体的内化能力提高。用共包封的脂质体免疫诱导OVA特异性Th 1偏向的免疫，其在加强注射后持续8个月。随后用表达OVA的肿瘤细胞系E.G7攻击，证明用共包封双配体的脂质体免疫的小鼠具有显著较慢的肿瘤进展。肿瘤清除依赖于OVA特异性细胞毒性记忆T细胞。这些结果表明，脂质体共包封TLR 3和TLR 9配体和特异性癌抗原，可以开发作为预防性癌症疫苗。(C)2017爱思唯尔B. V.保留所有权利。
Nucleic acid-based Toll-like receptor (TLR) ligands are promising adjuvants and immunotherapeutic agents. Combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory. However, their short circulation time due to nuclease attack hampers their clinical performance. Liposomes offer inclusion of protein and nucleic acid-based drugs with high encapsulation efficiency and drug loading. Furthermore, they protect cargo from enzymatic cleavage while providing stability, and enhancing biological activity. Herein, we aimed to develop a liposomal carrier system co-encapsulating TLR3 (polyinosinic-polycytidylic acid; poly(I:C)) and TLR9 (oligodeoxynucleotides (ODN) expressing unmethylated CpG motifs; CpG ODN) ligands as immunoadjuvants together with protein antigen. To demonstrate that this depot system not only induce synergistic innate immune activation but also boost antigen-dependent immune response, we analyzed the potency of dual ligand encapsulated liposomes in long-term cancer protection assay. Data revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells. Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection. Subsequent challenge with OVA-expressing tumor cell line, E.G7, demonstrated that mice immunized with liposomes co-encapsulating dual ligands had significantly slower tumor progression. Tumor clearance was dependent on OVA-specific cytotoxic memory T-cells. These results suggest that liposomes co-encapsulating TLR3 and TLR9 ligands and a specific cancer antigen could be developed as a preventive cancer vaccine. (C) 2017 Elsevier B.V. All rights reserved.