Xia Wen, Zhou Qin, Wang Xinya, Yang Jingru, Ren Xinxin, Wu Jian, Zhang Xuyan, Liuwei Jingjing, Hu Han, Liu Binlei, Wang Yang
National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), College of Bioengineering, Hubei University of Technology, Wuhan, China.
National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), College of Bioengineering, Hubei University of Technology, Wuhan, China; Wuhan Binhui Biopharmaceutical Co., Ltd., Wuhan, China.
Virology. 2025 Sep;610:110580. doi: 10.1016/j.virol.2025.110580. Epub 2025 May 21.
Oncolytic virus therapy is a novel and promising approach in tumor immunotherapy. We have developed the oncolytic virus OH2 and completed its preclinical studies. This oncolytic virus is currently undergoing clinical trials in China (NMPA, 2018L02743) and the United States (FDA IND 27137) targeting various solid tumors. One of the main mechanisms by which the oncolytic virus exerts its antitumor effect is through the direct killing of tumor cells. In our previous studies, we found that the structural protein VP5 of oncolytic virus OH2 can induce apoptosis in A549 cells via the TP53I3 molecule. This study further investigates the solid tumor cell lines involved in the clinical trials of oncolytic virus OH2. We found that VP5 protein exhibits different functions depending on the tumor cell type. Stable expression of VP5 protein enhanced the cytotoxicity of UV-OH2 against BGC823, LoVo, and CT26 cells, while inhibiting its cytotoxicity against 4T1 and HeLa cells. To explore the differences in the cytotoxicity induced by VP5 protein in different tumor cells, we performed transcriptome sequencing on 4T1-VP5 cells and OH2-stimulated 4T1-VP5 cells, comparing them with 4T1 cells and OH2-stimulated 4T1 cells, respectively. We also compared the transcriptome sequencing results with those of A549 cells from previous studies. Through this, we identified nectin-3 as a differentially expressed gene associated with tumor cell killing induced by VP5 protein. Further studies on nectin-3 revealed that the structural protein VP5 of oncolytic virus OH2 regulates the expression of nectin-3 in tumor cells, thereby promoting or inhibiting tumor cell apoptosis.
溶瘤病毒疗法是肿瘤免疫治疗中一种新颖且有前景的方法。我们研发了溶瘤病毒OH2并完成了其临床前研究。这种溶瘤病毒目前正在中国（国家药品监督管理局，2018L02743）和美国（食品药品监督管理局研究性新药申请27137）针对多种实体瘤进行临床试验。溶瘤病毒发挥其抗肿瘤作用的主要机制之一是直接杀伤肿瘤细胞。在我们之前的研究中，我们发现溶瘤病毒OH2的结构蛋白VP5可通过TP53I3分子诱导A549细胞凋亡。本研究进一步调查了参与溶瘤病毒OH2临床试验的实体瘤细胞系。我们发现VP5蛋白根据肿瘤细胞类型表现出不同的功能。VP5蛋白的稳定表达增强了UV-OH2对BGC823、LoVo和CT26细胞的细胞毒性，同时抑制了其对4T1和HeLa细胞的细胞毒性。为了探究VP5蛋白在不同肿瘤细胞中诱导的细胞毒性差异，我们分别对4T1-VP5细胞和OH2刺激的4T1-VP5细胞进行了转录组测序，并将它们与4T1细胞和OH2刺激的4T1细胞进行比较。我们还将转录组测序结果与之前研究中的A549细胞的结果进行了比较。通过这一过程，我们确定nectin-3是与VP5蛋白诱导的肿瘤细胞杀伤相关的差异表达基因。对nectin-3的进一步研究表明，溶瘤病毒OH2的结构蛋白VP5调节肿瘤细胞中nectin-3的表达，从而促进或抑制肿瘤细胞凋亡。
