Coxsackievirus B3 Is an Oncolytic Virus with Immunostimulatory Properties That Is Active against Lung Adenocarcinoma
Coxsackievirus B3 Is an Oncolytic Virus with Immunostimulatory Properties That Is Active against Lung Adenocarcinoma
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DOI：
10.1158/0008-5472.can-11-3185
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发表时间：
2012-05-15
期刊：
影响因子：
11.2
通讯作者：
Tani, Kenzaburo
中科院分区：
文献类型：
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作者：
Miyamoto, Shohei;Inoue, Hiroyuki;Tani, Kenzaburo
虽然溶瘤病毒治疗是一种很有前途的抗癌治疗方法，但肿瘤选择性低阻碍了其抗肿瘤效果。为了确定一种有效的、选择性的溶瘤病毒疗法，我们对28株肠病毒进行了大规模的两步筛选，发现柯萨奇病毒B3 （CVB3）对9种人类非小细胞肺癌（NSCLC）细胞系具有特异性的溶瘤活性。cvb3介导的细胞毒性与病毒受体柯萨奇病毒和腺病毒受体以及衰变加速因子在NSCLC细胞上的表达呈正相关。体外实验表明，CVB3诱导细胞凋亡和磷酸肌苷3-激酶/Akt和丝裂原活化蛋白(MAP)/细胞外信号调节（ERK）激酶（MEK）存活信号通路，导致细胞毒性和调控CVB3复制。肿瘤内注射CVB3可在体内引起预先建立的NSCLC肿瘤的显著消退。此外，将CVB3注射到右侧的异种移植物中，导致左侧未注射的异种移植物明显持久消退，在左侧检测到复制能力强的CVB3。所有CVB3治疗均耐受良好，无治疗相关死亡。此外，在CVB3感染后，NSCLC细胞表达了丰富的细胞表面钙调蛋白，分泌ATP和易位的核外高迁移性组盒1，这是免疫原性细胞死亡所必需的。此外，肿瘤内给予CVB3显著募集自然杀伤细胞和粒细胞，这两种细胞都有助于抗肿瘤作用，如消耗试验、巨噬细胞和成熟树突状细胞进入肿瘤组织所示。总之，我们的研究结果表明CVB3是一种有效且耐受性良好的溶瘤剂，具有免疫刺激特性，对局部和转移性NSCLC都有活性。癌症Res;72 (10);2609 - 21所示。(c) 2012年aacr。
Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacy is hampered by low tumor selectivity. To identify a potent and selective oncolytic virotherapy, we carried out large-scale two-step screening of 28 enteroviral strains and found that coxsackievirus B3 (CVB3) possessed specific oncolytic activity against nine human non-small cell lung cancer (NSCLC) cell lines. CVB3-mediated cytotoxicity was positively correlated with the expression of the viral receptors, coxsackievirus and adenovirus receptor, and decay-accelerating factor, on NSCLC cells. In vitro assays revealed that the CVB3 induced apoptosis and phosphoinositide 3-kinase/Akt and mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of preestablished NSCLC tumors in vivo. Furthermore, administrations of CVB3 into xenografts on the right flank resulted in significantly durable regression of uninjected xenografts on the left flank, where replication-competent CVB3 was detected. All treatments with CVB3 were well tolerated without treatment-related deaths. In addition, after CVB3 infection, NSCLC cells expressed abundant cell surface calreticulin and secreted ATP as well as translocated extranuclear high-mobility group box 1, which are required for immunogenic cell death. Moreover, intratumoral CVB3 administration markedly recruited natural killer cells and granulocytes, both of which contributed to the antitumor effects as shown by depletion assays, macrophages, and mature dendritic cells into tumor tissues. Together, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC. Cancer Res; 72(10); 2609-21. (C) 2012 AACR.