Goad Dakota W, Nesmelova Anna Y, Yohe Laurel R, Grdzelishvili Valery Z
Department of Biological Sciences, University of North Carolina at Charlotte , Charlotte, North Carolina, USA.
Department of Bioinformatics and Genomics, University of North Carolina at Charlotte , Charlotte, North Carolina, USA.
J Virol. 2023 Sep 28;97(9):e0100523. doi: 10.1128/jvi.01005-23. Epub 2023 Sep 6.
Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies demonstrated that human PDAC cell lines are highly variable in their permissiveness to OVs. Mouse PDAC cell lines, which are widely used for examination of the adaptive immune responses during OV and other cancer therapies, have never been examined systematically for the impact of intertumoral heterogeneity (the differences observed between tumors in different patients) on OV virus efficacy. Here, we examined phenotypically and genotypically three commonly used allograftable mouse PDAC cell lines (C57BL6 genetic background): Panc02 (derived from chemically induced PDAC; also known as Pan02), and two cell lines originated from PDACs developed in two different KPC (Kras, Trp53, and PDX-1-Cre) mouse models. Our study (i) characterized the ability of a widely used attenuated oncolytic vesicular stomatitis virus VSV-ΔM51-GFP to infect, replicate in, and kill mouse PDAC cells; (ii) examined their innate antiviral responses; (iii) compared their permissiveness to a non-attenuated VSV-Mwt-GFP and chemotherapeutic drugs; and (iv) analyzed their karyotype and exome. Mouse PDAC cell lines showed high divergence in their permissiveness to VSV-ΔM51-GFP, which negatively correlated with their abilities to mount innate antiviral responses, while all three cell lines were highly permissive to VSV-Mwt-GFP. No correlation was found between resistance to VSV-ΔM51-GFP and chemotherapy. Also, mouse PDAC cell lines showed high divergence in their karyotype and exome. The exome analysis demonstrated that more VSV-ΔM51-GFP-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. IMPORTANCE Oncolytic virus (OV) therapy is a promising virus-based approach against various malignancies, including pancreatic ductal adenocarcinoma (PDAC). Our previous studies using various human PDAC cell lines demonstrated that they are highly variable in their permissiveness to OVs. In this study, we examined phenotypically and genotypically three commonly used allograftable mouse PDAC cell lines, which are widely used for examination of the adaptive immune responses during cancer therapies. Mouse PDAC cell lines showed high divergence in their permissiveness to oncolytic vesicular stomatitis virus (VSV), which negatively correlated with their abilities to mount innate antiviral responses. Also, we discovered that more VSV-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. Our study provides essential information about three model mouse PDAC cell lines and proposes a novel platform to study OV-based therapies against different PDACs in immunocompetent mice.
溶瘤病毒（OV）疗法是一种基于病毒的、有前景的治疗多种恶性肿瘤的方法，包括胰腺导管腺癌（PDAC）。我们之前的研究表明，人类PDAC细胞系对OVs的易感性差异很大。小鼠PDAC细胞系广泛用于研究OV和其他癌症治疗过程中的适应性免疫反应，但从未系统研究过肿瘤间异质性（不同患者肿瘤之间的差异）对OV病毒疗效的影响。在这里，我们从表型和基因型上研究了三种常用的可移植小鼠PDAC细胞系（C57BL6遗传背景）：Panc02（源自化学诱导的PDAC；也称为Pan02），以及另外两种源自两种不同KPC（Kras、Trp53和PDX-1-Cre）小鼠模型中产生的PDAC的细胞系。我们的研究（i）表征了一种广泛使用的减毒溶瘤水疱性口炎病毒VSV-ΔM51-GFP感染、在小鼠PDAC细胞中复制并杀死它们的能力；（ii）检测了它们的先天性抗病毒反应；（iii）比较了它们对非减毒VSV-Mwt-GFP和化疗药物的易感性；（iv）分析了它们的核型和外显子组。小鼠PDAC细胞系对VSV-ΔM51-GFP的易感性差异很大，这与它们产生先天性抗病毒反应的能力呈负相关，而所有三种细胞系对VSV-Mwt-GFP都高度易感。未发现对VSV-ΔM51-GFP的抗性与化疗之间存在相关性。此外，小鼠PDAC细胞系在核型和外显子组方面也存在很大差异。外显子组分析表明，更多对VSV-ΔM51-GFP易感的小鼠PDAC细胞系在多个重要的抗病毒基因（如TYK2、JAK2和JAK3）中存在突变。重要性 溶瘤病毒（OV）疗法是一种基于病毒的、有前景的治疗多种恶性肿瘤的方法，包括胰腺导管腺癌（PDAC）。我们之前使用各种人类PDAC细胞系的研究表明，它们对OVs的易感性差异很大。在这项研究中，我们从表型和基因型上研究了三种常用的可移植小鼠PDAC细胞系，这些细胞系广泛用于研究癌症治疗过程中的适应性免疫反应。小鼠PDAC细胞系对溶瘤水疱性口炎病毒（VSV）的易感性差异很大，这与它们产生先天性抗病毒反应的能力呈负相关。此外，我们发现更多对VSV易感的小鼠PDAC细胞系在多个重要的抗病毒基因（如TYK2、JAK2和JAK3）中存在突变。我们的研究提供了关于三种模型小鼠PDAC细胞系的重要信息，并提出了一个新的平台来研究在免疫健全的小鼠中针对不同PDAC的基于OV的疗法。
