Reovirus activates human dendritic cells to promote innate antitumor immunity
Reovirus activates human dendritic cells to promote innate antitumor immunity
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DOI：
10.4049/jimmunol.180.9.6018
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发表时间：
2008-05-01
影响因子：
4.4
通讯作者：
Melcher, Alan
中科院分区：
文献类型：
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作者：
Errington, Fiona;Steele, Lynette;Melcher, Alan
溶瘤病毒可以通过直接溶瘤或激活抗肿瘤免疫来发挥其抗肿瘤活性。尽管呼肠孤病毒目前正在临床研究中用于治疗局部或播散性癌症，但尚未解决其疗效的任何潜在免疫贡献。这是第一个研究呼肠孤病毒激活人类树突状细胞（DC）的能力的研究，树突状细胞是先天性和适应性免疫反应的关键调节因子。呼肠孤病毒诱导DC成熟并刺激促炎细胞因子IFN-α、TNF-α、IL-12 p70和IL-6的产生。呼肠孤病毒对DC的激活不依赖于病毒复制，而PKR和NF-κ B信号传导的阻断抑制了细胞因子的产生（但不抑制表型成熟）。在与自体NK细胞共培养后，呼肠孤病毒激活的DC上调IFN-γ的产生并增加NK细胞溶解活性。此外，呼肠孤病毒激活的DC与抗肿瘤T细胞的短期共培养也增强了T细胞细胞因子（IL-2和IFN-γ）的分泌，并诱导非Ag限制性肿瘤细胞杀伤。这些数据首次证明呼肠孤病毒直接激活人DC，并且呼肠孤病毒激活的DC不仅刺激NK细胞，而且刺激T细胞的先天性杀伤，这表明T细胞在溶瘤病毒诱导的局部肿瘤细胞死亡中的新的潜在作用。因此，DC对呼肠孤病毒的识别可触发先天效应器机制以补充病毒的直接细胞毒性，从而潜在地增强呼肠孤病毒作为治疗剂的功效。
Oncolytic viruses can exert their antitumor activity via direct oncolysis or activation of antitumor immunity. Although reovirus is currently under clinical investigation for the treatment of localized or disseminated cancer, any potential immune contribution to its efficacy has not been addressed. This is the first study to investigate the ability of reovirus to activate human dendritic cells (DC), key regulators of both innate and adaptive immune responses. Reovirus induced DC maturation and stimulated the production of the proinflammatory cytokines IFN-alpha, TNF-alpha, IL-12p70, and IL-6. Activation of DC by reovirus was not dependent on viral replication, while cytokine production (but not phenotypic maturation) was inhibited by blockade of PKR and NF-kappa B signaling. Upon coculture with autologous NK cells, reovirus-activated DC up-regulated IFN-gamma production and increased NK cytolytic activity. Moreover, short-term coculture of reovirus-activated DC with antologous T cells also enhanced T cell cytokine secretion (IL-2 and IFN-gamma) and induced non-Ag restricted tumor cell killing. These data demonstrate for the first time that reovirus directly activates human DC and that reovirus-activated DC stimulate innate killing by not only NK cells, but also T cells, suggesting a novel potential role for T cells in oncolytic virus-induced local tumor cell death. Hence reovirus recognition by DC may trigger innate effector mechanisms to complement the virus's direct cytotoxicity, potentially enhancing the efficacy of reovirus as a therapeutic agent.