Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping the tumor microenvironment. C57BL/6J wild type (WT) and Cxcl10 knockout mice (Cxcl10^−/−) were treated with diethylnitrosamine (DEN) and tetrachloromethane (CCl₄) to induce fibrosis-associated HCCs. Cxcl10 deficiency attenuated hepatocarcinogenesis by decreasing tumor cell proliferation as well as tumor vascularization and modulated tumor-associated extracellular matrix composition. Furthermore, the genetic inactivation of Cxcl10 mediated an alteration of the tumor-associated immune response and modified chemokine/chemokine receptor networks. The DEN/CCl₄-treated Cxcl10^−/− mice presented with a pro-inflammatory tumor microenvironment and an accumulation of anti-tumoral immune cells in the tissue. The most striking alteration in the Cxcl10^−/− tumor immune microenvironment was a vast accumulation of anti-tumoral T cells in the invasive tumor margin. In summary, our results demonstrate that CXCL10 exerts a non-redundant impact on several hallmarks of the tumor microenvironment and especially modulates the infiltration of anti-tumorigenic immune cells in HCC. In the era of microenvironment-targeted HCC therapies, interfering with CXCL10 defines a novel asset for further improvement of therapeutic strategies.

Background Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and progressive cancer that ranks the second most common liver cancer. To further understand molecular mechanisms of rise and progression of cholangiocarcinoma animal models are needed. Next to carcinogen-induced ICC-models or genetically engineered models, there are only few allograft or xenograft transplant models that claim challenging operative techniques or longer time periods for tumor development. Method Hep55.1C cells were injected in the liver of 6-8 weeks old C57/B6 male mice. Tumor growth was followed by weekly ultrasound. After two or four weeks respectively mice were sacrificed. ICC and the tumor microenvironment were characterized via qRT-PCR, histological characterization/ multiplex imaging, flow cytometry and RNAseq. Murine data were comprehensively correlated with human data. Results Tumor size was 0.6cm² or 1cm² on average after two or four weeks after transplantation with a prevalence 100%. Tumor tissue in comparison to surrounding tissue showed high expression of cholangiocyte markers but not hepatocyte markers or markers for hepatocellular carcinoma. Immunohistological staining revealed a strong and ubiquitous signal for Pan-Cytokeratin within the tumor but not the surrounding tissue in contrast to HNF4α that was upregulated in the surrounding tissue. The analysis of the tumor microenvironment revealed a strong human homology regarding proliferation, gene expression pattern, tumor-associated immune response and stromal composition. Conclusion We here present a new intrahepatic cholangiocarinoma mouse model with human homology. Tumor induction shows a 100% success rate with macroscopic tumor growth within few weeks. Our model is therefore most suitable to evaluate interventional therapies. Publication Date: 26 January 2022 (online) © 2022. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany