Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity.
Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity.
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DOI：
10.1016/j.omto.2023.04.006
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发表时间：
2023-06-15
期刊：
影响因子：
--
通讯作者：
Zhang, Junjie
中科院分区：
文献类型：
--
作者：
Xie, Jun;Wang, Shaowei;Zhong, Yunhong;Gao, Ming;Tian, Xuezhang;Zhang, Liting;Pan, Dongli;Qin, Qingsong;Wu, Bing;Lan, Ke;Sun, Zhi-Jun;Zhang, Junjie
正在评估编码各种转基因的溶瘤病毒（OV）用于癌症免疫治疗。细胞因子、免疫检查点抑制剂、肿瘤相关抗原和 T 细胞接合剂等多种因子已被用作转基因。这些修饰的主要目的是逆转免疫抑制的肿瘤微环境。相比之下，抑制 OV 复制并导致溶瘤活性次优的抗病毒限制因子受到的关注要少得多。在这里，我们报告鸟苷酸结合蛋白 1 (GBP1) 在 HSV-1 感染期间被有效诱导并限制 HSV-1 复制。从机制上讲，GBP1 重塑细胞骨架组织，阻止 HSV-1 基因组进入核。先前的研究已确定 IpaH9.8（一种细菌 E3 泛素连接酶）以 GBP 为目标进行蛋白酶体降解。因此，我们设计了溶瘤 HSV-1 来表达 IpaH9.8，并发现修饰后的 OV 能有效拮抗 GBP1，在体外复制到更高滴度，并在体内表现出优异的抗肿瘤活性。我们的研究采用了一种策略，通过针对限制因子来改善 OV 的复制并实现有希望的治疗效果。 Xie及其同事证明，溶瘤HSV-1会诱导GBP1表达，从而重塑细胞骨架组织，阻止HSV-1基因组进入核，从而限制病毒复制。他们设计了一种携带细菌 GBP1 降解剂的溶瘤单纯疱疹病毒，可有效拮抗 GBP1 并显示出改善的抗肿瘤活性。
Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced during HSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer in vitro and showed superior antitumor activity in vivo. Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy. Xie and colleagues have shown that oncolytic HSV-1 induces GBP1 expression, which remodels cytoskeletal organization to impede the nuclear entry of HSV-1 genome, thereby restricting viral replication. They have engineered an oncolytic herpes simplex virus carrying a bacterial GBP1 degrader, which effectively antagonizes GBP1 and shows improved antitumor activity.
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