Measles virus induces oncolysis of mesothelioma cells and allows dendritic cells to cross-prime tumor-specific CD8 response
Measles virus induces oncolysis of mesothelioma cells and allows dendritic cells to cross-prime tumor-specific CD8 response
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DOI：
10.1158/0008-5472.can-07-6265
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发表时间：
2008-06-15
期刊：
影响因子：
11.2
通讯作者：
Gregoire, Marc
中科院分区：
文献类型：
--
作者：
Gauvrit, Anne;Brandler, Samantha;Gregoire, Marc
尽管传统的药物和手术治疗，恶性胸膜间皮瘤（MPM）仍然无法治愈。肿瘤病毒疗法（即，用于癌症治疗的有复制能力的病毒的用途）目前正在临床试验中探索。在这项研究中，我们调查了一种新的溶瘤病毒剂，减毒活麻疹病毒（MV）株来自埃德蒙斯顿疫苗谱系（施瓦茨株）的免疫潜力。我们评估了MV疫苗株对间皮瘤肿瘤细胞的溶瘤活性和免疫佐剂特性。在一组来自MPM患者胸腔积液的间皮瘤细胞上研究了MV的增殖性、合胞体形成和细胞溶解活性。我们观察到，MV感染优先MPM细胞系相比，非转化的间皮细胞，导致一个有效的杀死一个显着部分的肿瘤细胞。通过形成多核细胞聚集体（合胞体）也证明了细胞减少活性。MPM细胞系对麻疹感染的易感性通过分析MV疫苗受体（CD46）的细胞表面表达来评估。我们还评估了MV感染间皮瘤细胞是否能引起自体抗肿瘤免疫应答。我们发现，MV施瓦茨株诱导感染的间皮瘤细胞，这是有效地吞噬树突状细胞（DC）的凋亡细胞死亡。DC负载MV感染的MPM细胞诱导DC自发成熟，如通过增加MHC和共刺激分子的表达以及促炎细胞因子的产生沿着。通过负载MV感染的MPM细胞的DC引发自体T细胞导致肿瘤特异性CD8 T细胞的显著增殖。总之，这些数据强烈支持溶瘤MV作为间皮瘤癌症的有效治疗剂的潜力。
Despite conventional medical and surgical treatments, malignant pleural mesothelioma (MPM) remains incurable. Oncovirotherapy (i.e., the use of replication-competent virus for cancer treatment) is currently explored in clinical trials. In this study, we investigated the antineoplastic potential of a new oncolytic viral agent, a live-attenuated measles virus (MV) strain derived from the Edmonston vaccine lineage (Schwarz strain). We evaluated both oncolytic activity and immunoadjuvant properties of the MV vaccine strain on mesothelioma tumor cells. Infectivity, syncytium formation, and cytolytic activity of MV were studied on a panel of mesothelioma cells derived from pleural effusions of MPM patients. We observed that MV infected preferentially MPM cell lines in comparison with nontransformed mesothelial cells, leading to an efficient killing of a significant fraction of tumor cells. A cytoreductive activity was also evidenced through formation of multinuclear cellular aggregates (syncytia). The susceptibility of MPM cell lines to measles infection was assessed by the analysis of cell surface expression of the MV vaccine receptor (CD46). We also evaluated whether MV infection of mesothelioma cells could elicit an autologous antitumor immune response. We showed that MV Schwarz strain induced apoptotic cell death of infected mesothelioma cells, which were efficiently phagocytosed by dendritic cells (DC). Loading of DCs with MV-infected MPM cells induced DC spontaneous maturation, as evidenced by the increased expression of MHC and costimulatory molecules along with the production of proinflammatory cytokines. Priming of autologous T cells by DCs loaded with MV-infected MPM cells led to a significant proliferation of tumor-specific CD8 T cells. Altogether, these data strongly support the potential of oncolytic MV as an efficient therapeutic agent for mesothelioma cancer.