文章：

通过删除病毒cGAMP特异性核酸酶增强痘病毒介导的抗肿瘤免疫应答

Improving poxvirus-mediated antitumor immune responses by deleting viral cGAMP-specific nuclease 

原文发布日期：2023-04-04 

英文摘要：

cGAMP-specific nucleases (poxins) are a recently described family of proteins dedicated to obstructing cyclic GMP-AMP synthase signaling (cGAS), an important sensor triggered by cytoplasmic viral replication that activates type I interferon (IFN) production. The B2R gene of vaccinia viruses (VACV) codes for one of these nucleases. Here, we evaluated the effects of inactivating the VACV B2 nuclease in the context of an oncolytic VACV. VACV are widely used as anti-cancer vectors due to their capacity to activate immune responses directed against tumor antigens. We aimed to elicit robust antitumor immunity by preventing viral inactivation of the cGAS/STING/IRF3 pathway after infection of cancer cells. Activation of such a pathway is associated with a dominant T helper 1 (Th1) cell differentiation of the response, which benefits antitumor outcomes. Deletion of the B2R gene resulted in enhanced IRF3 phosphorylation and type I IFN expression after infection of tumor cells, while effective VACV replication remained unimpaired, both in vitro and in vivo. In syngeneic mouse tumor models, the absence of the VACV cGAMP-specific nuclease translated into improved antitumor activity, which was associated with antitumor immunity directed against tumor epitopes. 

摘要翻译： 

cGAMP特异性核酸酶（poxins）是近期发现的一个蛋白质家族，其功能专司阻断环GMP-AMP合成酶信号通路（cGAS）。该通路作为重要感应机制，可由细胞质内的病毒复制激活，进而启动I型干扰素（IFN）的产生。痘苗病毒（VACV）的B2R基因编码了这类核酸酶之一。本研究评估了在溶瘤痘苗病毒中灭活VACV B2核酸酶的效果。痘苗病毒因其能激活针对肿瘤抗原的免疫应答而被广泛用作抗癌载体。我们旨在通过阻止癌细胞感染后cGAS/STING/IRF3通路被病毒失活，从而激发强劲的抗肿瘤免疫。该通路的激活与辅助性T细胞1（Th1）优势分化的免疫应答相关，这种分化有利于抗肿瘤效果。B2R基因的缺失在肿瘤细胞感染后增强了IRF3磷酸化和I型IFN表达，而VACV的有效复制在体外和体内均未受影响。在同系小鼠肿瘤模型中，VACV cGAMP特异性核酸酶的缺失显著提升了抗肿瘤活性，这种活性与针对肿瘤表位的抗肿瘤免疫密切相关。

原文链接：

Improving poxvirus-mediated antitumor immune responses by deleting viral cGAMP-specific nuclease