The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment

Abstract

Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials.

Keywords: hepatocellular carcinoma; immune checkpoint inhibitors; immune checkpoint molecules; immune microenvironment.

Figure 1

The liver as an immunological organ. Because of its distinctive structure and specific blood supply route, the liver preserves a unique immune microenvironment. The liver sinusoidal endothelial cells (LSECs) form the fenestrated wall of the liver sinusoid and control the trafficking of molecules and cells from the liver parenchyma to the blood. At the sinusoids, circulating lymphocytes interact with antigens presented by endothelial cells, Kupffer cells (KCs), and liver resident dendritic cells (DCs), and, through fenestrations, they can access to the Disse space to get in touch with hepatocytes and hepatic stellate cells (HSCs). During liver injury or infection, a local inflammatory response is triggered as a result of the release of inflammatory cytokines (IL-6, IL-1β, and TGF-β) and chemokines (CXCL1, CXCL2, and CXCL8), leading to tissue damage and HCC development. Specifically, KCs and M1 macrophages produce IL-6 and TGF-β, which induce hepatocytes proliferation and resistance to apoptosis, and trigger the hepatocytes epithelial–mesenchymal transition (EMT) process and the differentiation of HSCs in collagen-producing myofibroblasts that promote fibrosis. Hepatocytes are mainly responsible for the production of the C-reactive protein supporting inflammation. M1 macrophages also release IL-1β, which enhances PD-L1 expression on hepatocytes resulting in T cells exhaustion and tumor development.

Figure 2

Schematic illustration of immune inhibitory interactions in the liver hepatocellular carcinoma microenvironment. Tumor-specific infiltrating CD4 T helper cells exhibit a great expression of immune checkpoint molecules programmed cell death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and mucin domain molecule 3 (TIM-3), whereas tumor-specific infiltrating CD8 T cells show a high expression of PD-1, CTLA-4, TIM-3, and lymphocyte activating gene 3 protein (LAG-3) on their surface. High levels of PD-1 and CTLA-4 are also displayed on the B cell surface. The interaction between PD-1 and its ligand PD-L1 expressed on hepatocytes, Kupffer cells (KCs), and hepatic stellate cells (HSCs) promotes T and B cell inhibition and induces CD8 T cells apoptosis. CTLA-4 inhibits immune functions favoring tumor growth. TIM-3 is involved in immune response regulation and immune tolerance induction. Besides T cells, tumor associated macrophages (TAMs) and natural killer (NK) cells markedly express TIM-3.

Figure 3

Schematic diagram of immune checkpoint expressions and their inhibitors.

Figure 4

Development and clinical trials of immune checkpoint inhibitors as single agents or in combination with other treatments for HCC from 2013 to 2021.