Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy
Oncolytic adenovirus programmed by synthetic gene circuit for cancer immunotherapy
复制标题
DOI：
10.1038/s41467-019-12794-2
复制
发表时间：
2019-10-22
影响因子：
16.6
通讯作者：
Xie, Zhen
中科院分区：
文献类型：
--
作者：
Huang, Huiya;Liu, Yiqi;Xie, Zhen
提高溶瘤病毒疗法的疗效仍然具有挑战性，这是由于难以提高针对癌症的特异性和免疫应答以及对其群体动态的了解有限。在这里，我们构建了可编程和模块化的合成基因电路，以控制腺病毒复制和免疫效应物的释放选择性地在肝细胞癌细胞中响应于多个启动子和microRNA输入。通过小鼠模型实验和计算机模拟，我们发现可复制的腺病毒比不可复制的腺病毒具有上级肿瘤杀伤功效。我们观察到通过结合肿瘤溶解和免疫调节剂的分泌，在免疫活性小鼠模型中促进局部淋巴细胞细胞毒性和系统接种的协同作用。此外，我们的计算模拟表明，编码免疫调节剂的溶瘤病毒可以发挥比溶瘤病毒和免疫效应物的组合治疗更强大的治疗功效。我们的研究结果提供了一种有效的策略来工程化溶瘤腺病毒，这可能导致各种癌症的创新免疫疗法。
Improving efficacy of oncolytic virotherapy remains challenging due to difficulty increasing specificity and immune responses against cancer and limited understanding of its population dynamics. Here, we construct programmable and modular synthetic gene circuits to control adenoviral replication and release of immune effectors selectively in hepatocellular carcinoma cells in response to multiple promoter and microRNA inputs. By performing mouse model experiments and computational simulations, we find that replicable adenovirus has a superior tumor-killing efficacy than non-replicable adenovirus. We observe a synergistic effect on promoting local lymphocyte cytotoxicity and systematic vaccination in immunocompetent mouse models by combining tumor lysis and secretion of immunomodulators. Furthermore, our computational simulations show that oncolytic virus which encodes immunomodulators can exert a more robust therapeutic efficacy than combinatorial treatment with oncolytic virus and immune effector. Our results provide an effective strategy to engineer oncolytic adenovirus, which may lead to innovative immunotherapies for a variety of cancers.