Therapeutic targeting of cancer-associated fibroblasts with oncolytic virus in preclinical models of intrahepatic cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy with limited effective therapies. Treatment resistance is partly due to activated cancer-associated fibroblasts (CAFs), which induce pro-tumor signaling and formation of a highly fibrotic tumor microenvironment. CAFs exist on a functional spectrum of subtypes and are difficult to target in vivo. Oncolytic viruses (OVs) can destroy pro-tumor CAFs and reduce fibrosis. We hypothesized that OV infection both lyses CAFs and reprograms surviving CAFs toward a less tumorigenic phenotype. Using in vitro models with CAFs from patient-derived xenograft (PDX) and syngeneic tumors, we evaluated the effects of Vaccinia (VV) and vesicular stomatitis viruses (VSV) and found that OVs killed iCCA cells and CAFs, while also reducing pro-tumor CAF signaling. In vivo, subcutaneous PDX and syngeneic models evaluated OV efficacy, tumor architecture, and CAF function. OVs effectively killed iCCA cells and CAFs, alongside a significant reduction of pro-tumorigenic signaling from syngeneic CAFs. Tumor growth abrogation correlated with decreased inflammatory CAF signaling, namely, hepatocyte growth factor (HGF) production. Notably, HGF enhanced OV tropism, while OV infection reduced HGF expression, suggesting a CAF antiviral defense that also limits pro-tumor signaling. These findings suggest a dual cytotoxic and reprogramming role for OVs in the iCCA microenvironment.