Syngeneic Murine Models with Distinct Immune Microenvironments Represent Subsets of Human Intrahepatic Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a poorly immunogenic malignancy with limited overall survival. Syngeneic, immunocompetent mouse models of CCA are an essential tool to elucidate the tumor immune microenvironment (TIME), understand mechanisms of tumor immune evasion, and test novel immunotherapeutic strategies. Hence, the scope of this study was to develop and characterize immunocompetent CCA models with distinct genetic drivers, and correlate tumor genomics, immunobiology, and therapeutic response. A multifaceted approach including scRNA-seq, CITE-Seq, whole exome and RNA sequencing was employed. Mouse variants were compared to human variants from human datasets. FDA-approved PD-1/PD-L1 antibodies were tested in humanized PD-1/PD-L1 mice (HuPD-H1). A genetic mouse model of intrahepatic CCA driven by intrabiliary transduction of Fbxw7 delta F/Akt that mimics human CCA was generated. From the Fbxw7 delta F/Akt tumors, a murine cell line (FAC) and syngeneic murine model with genetic and phenotypic characteristics of human CCA were developed. Established SB1 (YAP/Akt) and KPPC (KrasG12Dp53L/L) models were compared to the FAC model.