Adjuvant Activity Enhanced by Cross-Linked CpG-Oligonucleotides in β-Glucan Nanogel and Its Antitumor Effect
Adjuvant Activity Enhanced by Cross-Linked CpG-Oligonucleotides in β-Glucan Nanogel and Its Antitumor Effect
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DOI：
10.1021/acs.bioconjchem.6b00675
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发表时间：
2017-02-01
影响因子：
4.7
通讯作者：
Sakurai, Kazuo
中科院分区：
文献类型：
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作者：
Miyamoto, Noriko;Mochizuki, Shinichi;Sakurai, Kazuo
肿瘤疫苗能够通过产生和激活细胞毒性T淋巴细胞(CTL)直接清除肿瘤细胞。为了获得有效的CTL活性和诱导Th1反应，必须同时给予适当的佐剂和抗原。CpG-ODN是Toll样受体9(TLR9)的配体，能强烈诱导Th1反应。在我们之前的研究中，我们利用ODN与β-葡聚糖SPG形成复合物的方式开发了CpG-ODN递送系统，称为CpG/SPG，并证明了CpG/SPG可诱导高Th1反应。在这项研究中，我们通过DNA DNA杂交(交联型(CL)-CpG)制备了一种由CpG/SPG复合物制成的纳米凝胶。CL-CpG与卵清蛋白(OVA)联合免疫可诱导更强的抗原特异性Th1反应。预先免疫CL-CpG和OVA的小鼠肿瘤生长延迟时间较长，肿瘤接种后存活率提高。这些免疫诱导可以归因于纳米凝胶结构中的β-葡聚糖识别位点的尺寸增大和簇效应相结合而改善了细胞的摄取。换句话说，CL-CpG的颗粒性质，而不是CpG/SPG的半柔性棒状构象，增强了癌症疫苗的效力。结果表明，CL-CpG可作为一种有效的疫苗佐剂用于癌症和传染病的治疗。
Cancer vaccine has the ability to directly eradicate tumor cells by creating and activating cytotoxic T lymphocytes (CTLs). To achieve efficient CTL activity and to induce Th1 responses, it is essential to administer an appropriate adjuvant as well as an antigen. CpG-ODN is known as a ligand of Toll-like receptor 9 (TLR9) and strongly induces Th1 responses. In our previous study, we developed a CpG-ODN delivery system by use of the formation of complexes between ODN and a beta-glucan SPG, denoted as CpG/SPG, and demonstrated that CpG/SPG induces high Th1 responses. In this study, we created a nanogel made from CpG/SPG complexes through DNA DNA hybridization (cross-linked (CL)-CpG). Immunization with CL-CpG induced much stronger antigen-specific Th1 responses in combination with the antigenic protein ovalbumin (OVA) than that with CpG/SPG. Mice preimmunized with CL-CpG and OVA exhibited a long delay in tumor growth and an improved survival rate after tumor inoculation. These immune inductions can be attributed to the improvement of cellular uptake by the combination of increased size and the cluster effect of the beta-glucan recognition site in the nanogel structure. In other words, the particle nature of CL-CpG, instead of the semiflexible rod conformation of CpG/SPG, enhanced the efficacy of a cancer vaccine. The present results indicate that CL-CpG can be used as a potent vaccine adjuvant for the treatment of cancers and infectious diseases.