In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI) to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate-and eventually the long-lasting adaptive immunity against cancer.

中文翻译：

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溶瘤痘苗病毒表达DAI可增强病毒的免疫原性并增强抗肿瘤免疫力。

在溶瘤病毒疗法中，病毒激活免疫系统的能力是长期抗肿瘤作用的关键属性。牛痘病毒具有所有溶瘤病毒中最强的溶瘤活性之一。然而，主要由于其免疫抑制性质，其刺激抗肿瘤免疫的能力不是最佳的。为克服此问题，我们开发了溶瘤性VV，该溶瘤性VV表达IFN调节因子（DAI）的细胞内模式识别受体DNA依赖性激活剂，以增强先天免疫系统并激活肿瘤中的适应性免疫细胞。我们表明感染表达DAI的VV增加了与重要的免疫途径有关的几个基因的表达。用DAI武装的VV治疗导致小鼠的同基因黑素瘤肿瘤的大小显着减少。当小鼠受到相同肿瘤的攻击时，经DAI-VV处理的小鼠完全排斥了新肿瘤的生长，这表明已建立了针对肿瘤的免疫力。我们还显示，在用人外周血单核细胞人源化的DAI-VV处理的小鼠中，人黑素瘤肿瘤生长的控制得到增强，人T细胞水平升高。我们得出结论，溶瘤性VV表达DAI是扩大溶瘤性痘苗病毒的疫苗效力以触发先天性以及最终持久的针对癌症的适应性免疫的有前途的方法。我们还显示，在用人外周血单核细胞人源化的DAI-VV处理的小鼠中，人黑素瘤肿瘤生长的控制得到增强，人T细胞水平升高。我们得出结论，溶瘤性VV表达DAI是扩大溶瘤性痘苗病毒的疫苗效力以触发先天性以及最终持久的针对癌症的适应性免疫的有前途的方法。我们还显示，在用人外周血单核细胞人源化的DAI-VV处理的小鼠中，人黑素瘤肿瘤生长的控制得到增强，人T细胞水平升高。我们得出结论，溶瘤性VV表达DAI是扩大溶瘤性痘苗病毒的疫苗效力以触发先天性以及最终持久的针对癌症的适应性免疫的有前途的方法。