Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity.

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI:10.1016/j.omto.2023.04.006
Jun Xie, Shaowei Wang, Yunhong Zhong, Ming Gao, Xuezhang Tian, Liting Zhang, Dongli Pan, Qingsong Qin, Bing Wu, Ke Lan, Zhi-Jun Sun, Junjie Zhang
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Abstract

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.

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携带细菌GBP1降解物的溶瘤性单纯疱疹病毒提高了抗肿瘤活性。
编码多种转基因的溶瘤病毒(OVs)正在被评估用于癌症免疫治疗。多种因子,如细胞因子、免疫检查点抑制剂、肿瘤相关抗原和T细胞接合物已被用作转基因。这些修饰主要是为了逆转免疫抑制的肿瘤微环境。相比之下,抑制OVs复制并导致次优溶瘤活性的抗病毒限制因子受到的关注要少得多。在这里,我们报道了鸟苷结合蛋白1 (GBP1)在HSV-1感染期间被有效诱导并限制HSV-1的复制。在机制上,GBP1重塑细胞骨架组织以阻止HSV-1基因组的核进入。先前的研究已经证实,细菌E3泛素连接酶IpaH9.8靶向GBPs进行蛋白酶体降解。因此,我们设计了一种溶瘤性HSV-1来表达IpaH9.8,并发现修饰后的OV有效地拮抗GBP1,在体外复制到更高的滴度,并在体内表现出优异的抗肿瘤活性。我们的研究特点是通过靶向一个限制因子来改善OVs的复制,并取得了有希望的治疗效果。
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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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