Abstract
Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cause of cancer, and ranks fourth among the causes of cancer-related death [1]
The first drugs of this class tested in hepatocellular carcinoma (HCC) were tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a PD-1 antibody [48,51]
Anti-CTLA-4-associated injury is typically a granulomatous hepatitis with severe globular necrotic and inflammatory activity and lymphocyte T CD8 cells activation, while the histological pattern of liver damage associated with use of anti-PD-1/PD-L1 agents is more heterogeneous, showing a spotty and confluent necrosis and mild-to-moderate lobular and periportal inflammatory activity, involving both CD4 and CD8 lymphocytes in equal proportions [85]
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cause of cancer, and ranks fourth among the causes of cancer-related death [1]. Non-Alcoholic Fatty Liver Disease (NAFLD), the hepatological aspect of the metabolic syndrome, has been recognised as a relevant cause of advanced chronic liver disease, and the fastest growing cause of cirrhosis and HCC in Western countries [2]. HCC represents a unique and peculiar neoplastic setting, as in up to 80% of cases it arises on the background of cirrhosis and chronic inflammation, which is considered an important factor involved in cancer progression [4]. Precise molecular links between inflammation and HCC have not yet been fully elucidated, most data rely on the activation of the tumour necrosis factor-nuclear factor-κB axis, transcription target STAT3 and janus kinases activation as procarcinogenetic in the liver, while another player recently identified in this field is the inflammasome, a multiprotein complex and sensor of cellular damage [5,6].
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