Pipperger Lisa, Riepler Lydia, Kimpel Janine, Siller Anita, Stoitzner Patrizia, Bánki Zoltán, von Laer Dorothee
Institute of Virology, Medical University of Innsbruck, Innsbruck, Austria.
Central Institute of Blood Transfusion and Immunology, University Hospital Innsbruck, Innsbruck, Austria.
Oncoimmunology. 2021 Aug 31;10(1):1959140. doi: 10.1080/2162402X.2021.1959140. eCollection 2021.
Oncolytic viruses (OVs) can eradicate tumor cells and elicit antitumor immunity. VSV-GP, a chimeric vesicular stomatitis virus (VSV) with the glycoprotein (GP) of the lymphocytic choriomeningitis virus, is a promising new OV candidate. However, the interaction of VSV-GP with host immune cells is not fully understood. Dendritic cells (DCs) are essential for inducing efficient antitumor immunity. Thus, we aimed to investigate the interaction of VSV-GP with different murine and human DCs subsets in direct comparison to the less cytopathic variant VSV-dM51-GP and wild type VSV. Immature murine bone marrow-derived DCs (BMDCs) were equally infected and killed by VSV and VSV-GP. Human monocyte-derived DCs (moDCs) were more permissive to VSV. Interestingly, VSV-dM51-GP induced maturation instead of killing in both BMDCs and moDCs as well as a pronounced release of pro-inflammatory cytokines. Importantly, matured BMDCs and moDCs were no longer susceptible to VSV-GP infection. Mouse splenic conventional DC type 1 (cDC1) could be infected by VSV and VSV-GP to a higher extent than cDC2. Systemic infection of mice with VSV-GP and VSV-dM51-GP resulted in strong activation of cDCs despite low infection rates in spleen and tumor tissue. Human blood cDC1 were equally infected by VSV and VSV-GP, whereas cDC2 showed preferential infection with VSV. Our study demonstrated differential DC infection, activation, and cytokine production after the treatment with VSV and VSV-GP variants among species and subsets, which should be taken into account when investigating immunological mechanisms of oncolytic virotherapy in mouse models and human clinical trials.
溶瘤病毒（OVs）可根除肿瘤细胞并引发抗肿瘤免疫。VSV-GP是一种嵌合水疱性口炎病毒（VSV），带有淋巴细胞性脉络丛脑膜炎病毒的糖蛋白（GP），是一种很有前景的新型溶瘤病毒候选物。然而，VSV-GP与宿主免疫细胞的相互作用尚未完全了解。树突状细胞（DCs）对于诱导有效的抗肿瘤免疫至关重要。因此，我们旨在直接比较细胞病变性较小的变体VSV-dM51-GP和野生型VSV，研究VSV-GP与不同的小鼠和人类DCs亚群之间的相互作用。未成熟的小鼠骨髓来源的DCs（BMDCs）被VSV和VSV-GP同等感染并杀死。人单核细胞来源的DCs（moDCs）对VSV更敏感。有趣的是，VSV-dM51-GP在BMDCs和moDCs中诱导成熟而非杀伤，以及促炎细胞因子的显著释放。重要的是，成熟的BMDCs和moDCs不再易受VSV-GP感染。小鼠脾脏传统1型DC（cDC1）比cDC2更容易被VSV和VSV-GP感染。尽管在脾脏和肿瘤组织中的感染率较低，但用VSV-GP和VSV-dM51-GP对小鼠进行全身感染会导致cDCs的强烈激活。人血cDC1被VSV和VSV-GP同等感染，而cDC2显示对VSV有优先感染。我们的研究表明，在物种和亚群中用VSV和VSV-GP变体处理后，DCs的感染、激活和细胞因子产生存在差异，在小鼠模型和人类临床试验中研究溶瘤病毒疗法的免疫机制时应考虑到这一点。
