Delta-24-RGD oncolytic adenovirus elicits anti-glioma immunity in an immunocompetent mouse model.
Delta-24-RGD oncolytic adenovirus elicits anti-glioma immunity in an immunocompetent mouse model.
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DOI：
10.1371/journal.pone.0097407
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Fueyo J
中科院分区：
文献类型：
--
作者：
Jiang H;Clise-Dwyer K;Ruisaard KE;Fan X;Tian W;Gumin J;Lamfers ML;Kleijn A;Lang FF;Yung WK;Vence LM;Gomez-Manzano C;Fueyo J
新的证据表明，抗癌免疫参与了溶瘤病毒诱导的治疗效果。在这里，我们研究了Delta-24-RGD溶瘤腺病毒对天然和获得性抗胶质瘤免疫的影响。用免疫活性C57BL/6小鼠建立GL261-胶质瘤模型，进行Delta-24-RGD治疗。免疫组织化学和流式细胞术分析免疫细胞群的变化。通过对分离的小鼠脾细胞的功能研究，评价其抗胶质瘤免疫作用。通过动物存活分析评价病毒治疗的疗效。用体外卵白蛋白(OVA)模拟系统分析病毒对CD8+T细胞提呈肿瘤相关抗原的直接作用。Delta-24-RGD对小鼠脑胶质瘤细胞的细胞毒作用。病毒治疗GL261胶质瘤小鼠可引起先天免疫细胞和获得性免疫细胞的渗透，在肿瘤部位激发Th1免疫，导致特异性抗胶质瘤免疫，缩小肿瘤，延长动物生存时间。重要的是，病毒感染和干扰素γ增加了表达卵清蛋白的细胞向CD8+T细胞杂交瘤B3Z细胞递送卵清蛋白的能力，这一作用可被布雷菲尔丁A和蛋白酶体抑制剂阻断，表明其活性是通过生物合成和蛋白酶体途径实现的。我们的结果表明，Delta-24-RGD诱导了抗胶质瘤免疫，并首次提供了病毒感染直接增强肿瘤相关抗原呈递给免疫细胞的证据。
Emerging evidence suggests anti-cancer immunity is involved in the therapeutic effect induced by oncolytic viruses. Here we investigate the effect of Delta-24-RGD oncolytic adenovirus on innate and adaptive anti-glioma immunity. Mouse GL261-glioma model was set up in immunocompetent C57BL/6 mouse for Delta-24-RGD treatment. The changes of the immune cell populations were analyzed by immunohistochemistry and flow cytometry. The anti-glioma immunity was evaluated with functional study of the splenocytes isolated from the mice. The efficacy of the virotherapy was assessed with animal survival analysis. The direct effect of the virus on the tumor-associated antigen presentation to CD8+ T cells was analyzed with an in vitro ovalbumin (OVA) modeling system. Delta-24-RGD induced cytotoxic effect in mouse glioma cells. Viral treatment in GL261-glioma bearing mice caused infiltration of innate and adaptive immune cells, instigating a Th1 immunity at the tumor site which resulted in specific anti-glioma immunity, shrunken tumor and prolonged animal survival. Importantly, viral infection and IFNγ increased the presentation of OVA antigen in OVA-expressing cells to CD8+ T-cell hybridoma B3Z cells, which is blocked by brefeldin A and proteasome inhibitors, indicating the activity is through the biosynthesis and proteasome pathway. Our results demonstrate that Delta-24-RGD induces anti-glioma immunity and offers the first evidence that viral infection directly enhances presentation of tumor-associated antigens to immune cells.