Programmed death ligand 1 expression in hepatocellular carcinoma: A prognostic marker and therapeutic target for liver cancer?

The recent advent of immune checkpoint inhibitors represents a breakthrough in cancer treatment. “Immune checkpoint” refers to the inhibitory pathways maintaining self-tolerance and control of the immune response in peripheral tissues. Objective and durable clinical responses have been reported in several malignancies treated by immune checkpoint blockade, including melanoma, non-small cell lung carcinoma, squamous head and neck cancer, renal cancer, ovarian cancer, colorectal cancer, and Hodgkin lymphoma. More than 700 clinical studies involving monoclonal antibodies aimed at blocking the programmed death 1 (PD-1) axis or the cytotoxic Tlymphocyte antigen 4 axis are currently registered at the ClinicalTrials.gov site. Cancer treatment based on immune checkpoint blockade stems from the observation that oncogenesis is associated with the expression of tumor-associated antigens (TAAs). Since the discovery of the first melanoma-associated antigen, more than 400 TAAs have been reported. The interaction of TAAs and the host immune system includes immune surveillance, immune editing, and immune tolerance. Accordingly, while tumor cells with high TAA expression are eliminated, tumor cells with low TAA expression can proliferate; and in established malignancies, the tumor microenvironment leads to immune suppression and promotes tumor progression. Mechanisms of tumor immune suppression include expression of the PD-1 ligand (PD-L1). This protein interacts with activated T and B lymphocytes, natural killer cells, dendritic cells, and macrophages that in turn express PD-1, leading to regulatory T-cell proliferation and exhaustion of effector cells. Documented TAAs in hepatocellular carcinoma (HCC) are alpha-fetoprotein, glypican-3, melanoma-associated antigen A1, and the New York esophageal squamous cell carcinoma-1. More than 50% of cluster of differentiation 8-positive (CD8) T cells from patients with HCC recognize the overlapping peptides derived from these TAAs at a rate that is inversely correlated with HCC stage. However, despite the high rate of TAA recognition, the effector cell function evaluated by interferon-c secretion and cytolytic activity is impaired. At this point, it remains unclear whether, and to what extent, PD-1 blockade restores antitumor activity in patients with HCC. In this issue of HEPATOLOGY, Calderaro et al. report new data on the expression of PD-L1 in tumor cells and PD-1 in the tumor infiltrate in a large series of HCC. The authors observed that PD-L1 was expressed in 17% of tumors and that, among positive cases, the rate of PD-L1-positive tumor cells ranged from 1% to 30%. PD-L1 expression in tumor cells was associated with HCC progenitor subtype, characterized by poor clinical outcome. In keeping with this finding, PD-L1 expression was associated with common markers of aggressiveness and, above all, Abbreviations: CD, cluster of differentiation; HCC, hepatocellular carcinoma; PD-1, programmed death 1; PD-L1, programmed death ligand 1; TAA, tumor-associated antigen.