Mouse Models of Oncoimmunology in Hepatocellular Carcinoma

Abstract

Liver cancer is the fourth leading cause of cancer-related mortality worldwide and incidence is on the rise. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, with a complex etiology and limited treatment options. The standard-of-care treatment for patients with advanced HCC is sorafenib, a tyrosine kinase inhibitor that offers limited survival benefit. In the past years, therapeutic options for the treatment of advanced HCC have increased substantially, including additional multikinase inhibitors as well as immune checkpoint inhibitors. Nivolumab and pembrolizumab were approved in 2017 and 2018, respectively, as second-line treatment in advanced HCC. These drugs, both targeting the programmed death-1 pathway, demonstrate unprecedented results, with objective response rates of approximately 20%. However, the majority of patients do not respond, necessitating the identification of biomarkers of response and resistance to immunotherapy. With the recent success of immunotherapies in oncology, mouse models that better recapitulate the human disease and antitumor immune response are needed. This review lists ongoing clinical trials testing immunotherapy in HCC, briefly discusses the unique immunosuppressive environment of the liver, and then delves into the most applicable current murine model systems to study oncoimmunology within the context of HCC, including syngeneic, genetically engineered, and humanized models.

Figure 1:. Liver immunity overview.

Schematic depicting key functions of the different liver cell populations, hepatic parenchymal, non-parenchymal, myeloid, and lymphoid, in maintaining a balance between tolerogenic and effector responses against pathogens and malignant cells.

Figure 2:. Representative murine model system for oncoimmunology study (43).

1) Transfection of a commercial murine HCC cell line with PD-L1 or control plasmid. 2) Transfected HCC cells were co-cultured with murine splenic CD4⁺ and CD8⁺ T cells; cytokine profiling and proliferation assays were performed. 3) Syngeneic orthotopic implantation of transfected HCC cells into immunocompetent mice. Resultant untreated tumors were collected and processed for RNA immune profiling. In parallel, mice harboring orthotopic tumors were treated with vehicle, anti-PD-1 or anti-PD-1+sorafenib; tumor immune profiling and survival analysis were performed.