Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1.
Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1.
复制标题
通过抑制 Bach1 增强 HSV-1 介导的抗肿瘤免疫反应。
DOI：
10.1038/s41423-021-00824-3
复制
发表时间：
2022
影响因子：
24.1
通讯作者：
Cheng Genhong
中科院分区：
文献类型：
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作者：
Pan Chaohu;Cai Qiaomei;Li Xiaorong;Li Lili;Yang Liping;Chen Yu;Liu Junxiao;Liu Wancheng;Gao Meiling;Sui Tianqi;Wang Xiaoyang;Fan Huiming;Ruan Jiayin;Shi Yueyue;Chen Saihua;Cheng Lucy S;Liu Jiayong;Yang Heng;Cheng Genhong
背景2015年，单纯疱疹病毒1型(HSV-1)衍生的拉赫帕雷帕韦克(T-VEC)是美国食品和药物管理局(FDA)批准的第一种用于癌症治疗的溶瘤病毒。然而，它的抗肿瘤应用仅限于黑色素瘤的局部治疗，对HSV-1在癌细胞中复制的调节机制和相关的抗肿瘤免疫缺乏了解。我们假设增加HSV-1在肿瘤细胞中的复制能力会增强该病毒的抗肿瘤作用。方法通过功能筛选，系统地鉴定了HSV-1诱导的干扰素刺激基因，并阐明了BACH1抗HSV-1的机制。然后检测BACH1缺陷对HSV-1诱导的免疫原性细胞死亡的影响。结果我们鉴定了8个控制HSV-1复制的干扰素刺激基因(ISGs)，其中BTB和CnC同源1(BACH1)通过抑制ICP4、ICP27和UL39的转录而抑制HSV-1的复制。Bach1功能的丧失不仅增加了HSV-1的增殖，还促进了HSV-1诱导的细胞凋亡、HMGB1的分泌和肿瘤细胞中钙网织蛋白的暴露。更重要的是，FDA批准的下调BACH1的药物氯化血红素显著增强了HSV-1介导的抗肿瘤活性，并增加了肿瘤部位的T淋巴细胞浸润。结论我们的研究发现了BACH1的一种新的抗病毒活性，为提高溶瘤病毒HSV-1的临床疗效提供了新的策略。
BackgroundIn 2015, herpes simplex virus 1 (HSV-1)-derived talimogene laherparepvec (T-VEC) was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment. However, its antitumor application is limited to local treatment of melanoma, and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity. We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.MethodsWe systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1. Then, we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1. Furthermore, we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.ResultsWe identified eight IFN-stimulated genes (ISGs) controlling HSV-1 replication, among which BTB and CNC homology 1(BACH1) suppressed HSV-1 replication by inhibiting the transcription of ICP4, ICP27, and UL39. Loss ofBach1function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis, HMGB1 secretion, and calreticulin exposure in tumor cells. More importantly, hemin, an FDA-approved drug known to downregulate BACH1, significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.ConclusionsOur studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.