As the mechanisms underlying tumorigenesis become better understood, the dynamic roles of cellular components of the tumor microenvironment, and their cross-talk with tumor cells, have come to light as key drivers of disease progression and have emerged as important targets of new cancer therapies. In the field of oncolytic virus (OV) therapy, stromal cells have been considered as potential barriers to viral spread, thus limiting virus replication and therapeutic outcome. However, new evidence indicates that intratumoral fibroblasts could support virus replication. We have demonstrated in a rat model of stromal-rich intrahepatic cholangiocarcinoma (CCA) that vesicular stomatitis virus (VSV) can be localized within intratumoral hepatic stellate cells (HSCs), in addition to tumor cells, when the virus was applied via hepatic arterial infusion. Furthermore, VSV was shown to efficiently kill CCA cells and activated HSCs, and co-culture of CCA and HSCs increased viral titers. Interestingly, this effect is also observed when each cell type is cultured alone in a conditioned medium of the other cell type, indicating that secreted cell factors are at least partially responsible for this phenomenon. Partial reduction in sensitivity to type I interferons was observed in co-culture systems, providing a possible mechanism for the increased viral titers. Together, the results indicate that targeting activated HSCs with VSV could provide an additional mechanism of OV therapy, which, until now has not been considered. Furthermore, these findings suggest that VSV is a potentially powerful therapeutic agent for stromal-rich tumors, such as CCA and pancreatic cancer, both of which are very difficult to treat with conventional therapy and have a very poor prognosis.
随着肿瘤发生机制的日益明晰，肿瘤微环境中细胞成分的动态作用及其与肿瘤细胞的相互作用，已成为疾病进展的关键驱动因素，并成为新型癌症疗法的重要靶点。在溶瘤病毒治疗领域，基质细胞曾被视为病毒扩散的潜在屏障，从而限制病毒复制及治疗效果。然而，新证据表明肿瘤内成纤维细胞可能支持病毒复制。我们在富含基质的肝内胆管癌大鼠模型中发现，通过肝动脉输注水疱性口炎病毒后，该病毒不仅存在于肿瘤细胞内，还能定位于肿瘤内肝星状细胞。进一步研究显示，水疱性口炎病毒能有效杀伤胆管癌细胞和活化的肝星状细胞，且两者共培养可提高病毒滴度。值得注意的是，当两种细胞分别在对方条件培养基中单独培养时，同样观察到该效应，表明分泌性细胞因子至少部分介导了这一现象。共培养系统中观察到对I型干扰素敏感性的部分降低，这为病毒滴度升高提供了可能的机制解释。综上，研究结果表明利用水疱性口炎病毒靶向活化的肝星状细胞，可能为溶瘤病毒治疗提供全新机制，这一机制此前尚未被考虑。此外，这些发现提示水疱性口炎病毒对富含基质的肿瘤（如胆管癌和胰腺癌）具有潜在强效治疗作用，而此类肿瘤采用常规疗法极难治疗且预后极差。
肿瘤(癌症)患者之家