Oncolytic viruses have been considered promising cancer immunotherapies. However, oncovirotherapy agents impart durable responses in only a subset of cancer patients. Thus, exploring the cellular and molecular mechanisms underlying the heterogeneous responses in patients can provide guidance to develop more effective oncolytic virus therapies. Single-cell RNA sequencing (scRNA-seq) analysis of tumors responsive and non-responsive to oncovirotherapy revealed signatures of the tumor immune microenvironment associated with immune response. Thus, we designed and constructed an armed oncolytic virus OV-5A that expressed five genes with non-redundant functions. OV-5A treatment exhibits robust immune response against various tumors in multiple mouse models, peripheral blood mononuclear cell (PBMC)-patient derived xenograft (PDX) model, organoid-immune cell co-culture systems and patient tissue sections by activating a cooperative innate-adaptive immune response against tumor cells. scRNA-seq analysis of complete responder and partial responder to OV-5A treatment guided the design of combination therapy of OV-5A. This data-driven approach paves a innovative way to rationalize the design of oncolytic virus and multi-agent combination therapies.

中文翻译：

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武装溶瘤病毒和联合疗法的单细胞数据驱动设计，以激活针对癌症的协作先天适应性免疫。


溶瘤病毒被认为是有前途的癌症免疫疗法。然而，肿瘤病毒疗法药物仅在一部分癌症患者中产生持久的反应。因此，探索患者异质反应背后的细胞和分子机制可以为开发更有效的溶瘤病毒疗法提供指导。对肿瘤病毒疗法有反应和无反应的肿瘤的单细胞 RNA 测序 （scRNA-seq） 分析揭示了与免疫反应相关的肿瘤免疫微环境的特征。因此，我们设计并构建了一种武装溶瘤病毒 OV-5A，该病毒表达 5 个具有非冗余功能的基因。OV-5A 治疗通过激活针对肿瘤细胞的协作性先天适应性免疫反应，在多种小鼠模型、外周血单核细胞 （PBMC） -患者来源的异种移植物 （PDX） 模型、类器官免疫细胞共培养系统和患者组织切片中表现出针对各种肿瘤的强大免疫反应。对 OV-5A 治疗的完全缓解者和部分缓解的 scRNA-seq 分析指导了 OV-5A 联合治疗的设计。这种数据驱动的方法为溶瘤病毒和多药联合疗法的设计合理化铺平了一条创新道路。