Hepatocellular Carcinoma: Animal Models Available to Characterize Tumor Immunology and Optimize Treatment Development

Abstract

Hepatocellular carcinoma (HCC) is the second cause of cancer-related death worldwide with almost 1 million new cases per year. At the diagnosis, 70% of patients have only access to a palliative treatment [1,2] with few therapeutic options mostly represented by tyrosine kinase inhibitors such as sorafenib [3] and lenvatinib [4] in first line; regorafenib [5] and cabozantinib [6] in second line. HCC occurs on a cirrhotic liver in more than 90% of cases and liver is a singular organ from an immunological point of view. Cirrhosis modulates liver immune landscape through chronic alterations such as inflammation and fibrosis and these immune changes may induce aberrant immunotolerance through the activation of multiple pathways involving major immune functions such as antigen presentation or lymphocytes’ exhaustion. These modifications lead to failure to immunosurveillance systems and allow tumor initiation and progression [7]. For that reason, HCC seems to be a good candidate to immunostimulatory therapies aiming to restore anticancer immunity. These therapies are currently strongly studied in this pathology with the advent of monoclonal antibodies directed against immune checkpoints, especially against PD-1/PD-L1 pathway. Two new combination therapies particularly stand out: atezolizumab (anti-PD-L1) bevacizumab (anti-angiogenic) which is becoming the new standard in first line [8] and durvalumab (anti-PD-L1) tremelimumab (anti-CTLA4) [9]. Nonetheless, a large proportion of patients do not respond to these treatments and complex physiopathological mechanisms involved in HCC oncogenesis, as well as resistance pathways activated during these immunotherapies are still poorly understood.