Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation
Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation
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DOI：
10.1038/sj.onc.1210884
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发表时间：
2008-04-10
期刊：
影响因子：
8
通讯作者：
Fujiwara, T.
中科院分区：
文献类型：
--
作者：
Endo, Y.;Sakai, R.;Fujiwara, T.
树突状细胞（Dendritic cells，DC）是最强的抗原提呈细胞，通过直接的细胞间相互作用和细胞因子的产生，从死亡细胞获得细胞抗原和危险信号，启动抗肿瘤免疫应答。引发DC释放危险信号的肿瘤细胞死亡的最佳形式尚未完全了解。OBP- 301（端粒溶素）是一种端粒聚合酶特异性复制型腺病毒，可诱导选择性E1表达并专门杀死人类癌细胞。在这里，我们表明，OBP- 301复制产生的内源性危险信号分子，尿酸，在受感染的人肿瘤细胞，这反过来刺激DC产生干扰素-γ（IFN-γ）和白细胞介素12（IL- 12）。随后，IFN-γ释放上调肿瘤细胞中蛋白酶体激活剂PA 28的内源性表达，并导致细胞毒性T淋巴细胞的诱导。我们的数据表明，病毒介导的溶瘤作用可能是未成熟DC诱导抗人癌细胞特异性活性的有效刺激。
Dendritic cells ( DCs) are the most potent antigen-presenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell- to- cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP- 301 ( Telomelysin) is a telomerase-specific replication- competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP- 301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-gamma ( IFN-gamma) and interleukin 12 ( IL- 12). Subsequently, IFN-gamma release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T- lymphocytes. Our data suggest that virus- mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.