Identification of Two Distinct Immune Subtypes in Hepatitis B Virus (HBV)-Associated Hepatocellular Carcinoma (HCC)

HBV is the most common risk factor for HCC development, accounting for almost 50% of the cases worldwide. Despite significant advances in immunotherapy, there is limited information on the HBV-HCC tumor microenvironment (TME), which may influence the response to checkpoint inhib-itors. Here, we characterize the TME in a unique series of liver specimens from HBV-HCC patients to identify who might benefit from immunotherapy. By combining an extensive immunohisto-chemistry analysis with the transcriptomic profile of paired liver samples (tumor vs nontumorous tissue) from 12 well-characterized Caucasian patients with HBV-HCC, we identified two distinct tumor subtypes that we defined immune-high and immune-low. The immune-high subtype, seen in half of the patients, is characterized by a high number of infiltrating B and T cells in association with stromal activation, and a transcriptomic profile featuring inhibition of antigen presentation and CTL activation. All the immune-high tumors expressed high levels of CTLA-4 and low levels of PD-1, while PD-L1 was present only in 4 of 6 cases. In contrast, the immune-low subtype shows significantly lower lymphocyte infiltration and stromal activation. Outside the tumor, there were no differences between the two subtypes. This study identifies two distinctive immune subtypes in HBV-associated HCC, regardless of the microenvironment observed in the surrounding nontu-morous tissue, providing new insights into pathogenesis. These findings may be instrumental to identify patients who might benefit from immunotherapy.