Cross-Talk Between Tumor Cells and Stellate Cells Promotes Oncolytic VSV Activity in Intrahepatic Cholangiocarcinoma.

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.