Identification and validation of HCC-specific gene transcriptional signature for tumor antigen discovery

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide with a 5-year survival rate of approximately 5-6%1,2. Multiple etiological factors for HCC are known with an uneven geographical distribution. Globally, more than 50% of HCC cases can be attributed to hepatitis B virus (HBV) infection, more than 30% to hepatitis C virus (HCV) infection and approximately 15% can be associated with non-viral causes (i.e., alcohol, aflatoxins, metabolic liver diseases, steatosis and non-alcoholic fatty liver disease)3. Regardless the etiology, the overall prognosis for HCC patients is poor with a median survival of 14 months and less than 5% of symptomatic patients surviving more than 2 years1,2. A range of therapies are used in the management of HCC according to the extent and severity of liver disease. In early-stage HCC, surgery (i.e., tumor resection and liver transplantation) represents the standard treatment with a 5-year survival rate in 70% of treated patients4-6. However, the majority of HCC patients are diagnosed when disease precludes surgical approaches and only loco-regional therapies can be applied with limited survival benefits. Moreover, tumor recurrence is observed in 50 to 80% of patients at 5 years after treatment, with most relapses occurring within 2 years7. Therapeutic options in advanced unresectable HCC are limited to Sorafenib which is the only approved therapy confirmed to provide a limited increase in survival of 2.3-2.8 months8-11. In this framework, immunotherapeutic interventions, including cancer vaccines, may represent a novel and effective therapeutic tool for HCC. However, only few clinical trials have been conducted so far, showing efficient elicitation of immune response with limited clinical outcomes. One of the major reasons for such unsatisfactory results is due to low number of tumor antigens and epitopes specific for HCC to be employed in active and passive immunotherapy approaches12. Indeed, identification of "tumor-specific" target molecules suitable for therapeutic strategies represents a primary goal and a major challenge.