一种新型C型CpG寡脱氧核苷酸具有免疫刺激活性并增强抗肿瘤作用。
A Novel C Type CpG Oligodeoxynucleotide Exhibits Immunostimulatory Activity and Enhances Antitumor Effect .
作者信息
Li Tete, Wu Jing, Zhu Shan, Zang Guoxia, Li Shuang, Lv Xinping, Yue Wenjun, Qiao Yuan, Cui Jiuwei, Shao Yan, Zhang Jun, Liu Yong-Jun, Chen Jingtao
机构信息
Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
Cancer Center, The First Hospital of Jilin University, Changchun, China.
出版信息
Front Pharmacol. 2020 Feb 6;11:8. doi: 10.3389/fphar.2020.00008. eCollection 2020.
BACKGROUND
C type CpG oligodeoxynucleotides (CpG-C ODNs), possessing the features of both A type and B type CpG ODNs, exert a variety of immunostimulatory activities and have been demonstrated as an effective antitumor immunotherapy. Based on the structural characteristics, we designed 20 potential ODNs with the aim of synthesizing an optimal, novel CpG-C ODN specific to human and murine Toll-like receptor 9 (TLR9). We also sought to investigate the immunostimulatory and antitumor effects of the novel CpG-C ODN.
METHODS
Twenty potential CpG-C ODNs were screened for their ability to secrete interferon (IFN)-α, and interleukin (IL)-6 and tumor necrosis factor (TNF)-α production for the three most promising sequences were assayed in human peripheral blood mononuclear cells (PBMCs) by enzyme-linked immunosorbent assay (ELISA) or cytometric bead array assay. The functions of human and mouse B cells, and cytokine production in mice induced by the most promising sequence, HP06T07, were determined by flow cytometry and ELISA. Growth and morphology of tumor tissues in murine models inoculated with CT26 cells were analyzed by a growth inhibition assay and immunohistochemistry, respectively.
RESULTS
Among the 20 designed ODNs, HP06T07 significantly induced IFN-α, IL-6, and TNF-α secretion, and promoted B-cell activation and proliferation in a dose-dependent manner in human PBMCs and mouse splenocytes . Intratumoral injection of HP06T07 notably suppressed tumor growth and prolonged survival in the CT26 subcutaneous mouse model in a dose-dependent manner. HP06T07 administered nine times at 2-day intervals (I2) eradicated tumor growth at both primary and distant sites of CT26 tumors. HP06T07 restrained tumor growth by increasing the infiltration of T cells, NK cells, and plasmacytoid dendritic cells (pDCs).
CONCLUSIONS
HP06T07, a novel CpG-C ODN, shows potent immunostimulatory activity and suppresses tumor growth in the CT26 subcutaneous mouse model.
背景
C型CpG寡脱氧核苷酸（CpG-C ODNs）兼具A型和B型CpG ODNs的特征，具有多种免疫刺激活性，已被证明是一种有效的抗肿瘤免疫疗法。基于其结构特征，我们设计了20种潜在的ODNs，旨在合成一种针对人和小鼠Toll样受体9（TLR9）的最佳新型CpG-C ODN。我们还试图研究这种新型CpG-C ODN的免疫刺激和抗肿瘤作用。
方法
筛选20种潜在的CpG-C ODNs分泌干扰素（IFN）-α的能力，并通过酶联免疫吸附测定（ELISA）或细胞计数珠阵列测定法在人外周血单核细胞（PBMCs）中检测三种最有前景序列的白细胞介素（IL）-6和肿瘤坏死因子（TNF）-α的产生。通过流式细胞术和ELISA确定最有前景的序列HP06T07诱导的人和小鼠B细胞的功能以及小鼠体内的细胞因子产生。分别通过生长抑制试验和免疫组织化学分析接种CT26细胞的小鼠模型中肿瘤组织的生长和形态。
结果
在20种设计的ODNs中，HP06T07显著诱导IFN-α、IL-6和TNF-α的分泌，并以剂量依赖性方式促进人PBMCs和小鼠脾细胞中B细胞的活化和增殖。瘤内注射HP06T07以剂量依赖性方式显著抑制CT26皮下小鼠模型中的肿瘤生长并延长生存期。以2天间隔（I2）给予9次HP06T07可根除CT26肿瘤原发部位和远处部位的肿瘤生长。HP06T07通过增加T细胞、NK细胞和浆细胞样树突状细胞（pDCs）的浸润来抑制肿瘤生长。
结论
新型CpG-C ODN HP06T07具有强大的免疫刺激活性，并在CT26皮下小鼠模型中抑制肿瘤生长。
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