Immune checkpoint inhibition: prospects for prevention and therapy of hepatocellular carcinoma

Abstract

The global prevalence of liver cancer is rapidly rising, mostly as a result of the amplified incidence rates of viral hepatitis, alcohol abuse and obesity in recent decades. Treatment options for liver cancer are remarkably limited with sorafenib being the gold standard for advanced, unresectable hepatocellular carcinoma but offering extremely limited improvement of survival time. The immune system is now recognised as a key regulator of cancer development through its ability to protect against infection and chronic inflammation, which promote cancer development, and eliminate tumour cells when present. However, the tolerogenic nature of the liver means that the immune response to infection, chronic inflammation and tumour cells within the hepatic environment is usually ineffective. Here we review the roles that immune cells and cytokines have in the development of the most common primary liver cancer, hepatocellular carcinoma (HCC). We then examine how the immune system may be subverted throughout the stages of HCC development, particularly with respect to immune inhibitory molecules, also known as immune checkpoints, such as programmed cell death protein-1, programmed cell death 1 ligand 1 and cytotoxic T lymphocyte antigen 4, which have become therapeutic targets. Finally, we assess preclinical and clinical studies where immune checkpoint inhibitors have been used to modify disease during the carcinogenic process. In conclusion, inhibitory molecule-based immunotherapy for HCC is in its infancy and further detailed research in relevant in vivo models is required before its full potential can be realised.

Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents

“…These higher rates of Grade 3‐4 adverse events likely reflect additive effects of tissue autoantigen release as a result of tumour infiltration and/or viral damage in conjunction with ICI‐induced increase of autoreactive T cell activity. There have been a growing number of published studies designed to determine the effects of ICIs for the treatment of HCC . In one clinical study, HCC patients undergoing CTLA‐4 blockade with tremelimumab who were infected with HCV demonstrated a relatively good liver adverse event profile with only transient elevations of serum aminotransferases after the first dose of therapy …”

“…There have been a growing number of published studies designed to determine the effects of ICIs for the treatment of HCC. [59][60][61][62][63][64] In one clinical study, HCC patients undergoing CTLA-4 blockade with tremelimumab who were infected with HCV demonstrated a relatively good liver adverse event profile with only transient elevations of serum aminotransferases after the first dose of therapy. 65…”

IL‐25 protects against high‐fat diet‐induced hepatic steatosis in mice by inducing IL‐25 and M2a macrophage production

“…have shown that human umbilical vein endothelial cells and bronchial mucosa endothelial cells can also express IL‐25 . In the liver, hepatic IL‐10/IL‐33, TNF‐β and PD‐L1 may be produced by liver sinusoidal endothelial cells . We determined the direct effect of IL‐25 on mouse liver sinusoidal endothelial cells in vitro .…”

“…42 In the liver, hepatic IL-10/IL-33, 43 TNF-b 44 and PD-L1 45 may be produced by liver sinusoidal endothelial cells. 46 We determined the direct effect of IL-25 on mouse liver sinusoidal endothelial cells in vitro. After treatment, IL-25 induced a notable upregulation of IL-10 expression and a slight upregulation of IL-25 expression; however, IL-25 did not affect the expression of IL-33, TNF-b or PD-L1 (Supplementary figure 7f).…”

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

“…The multikinase inhibitors sorafenib and regorafenib are the only systemic treatments with proven survival benefits and they prolong the life expectancy of patients by 2 to 3 months (4). Immune-based approaches, including targeting of the immune checkpoint inhibitors programmed cell death (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), represent novel, promising therapeutic strategies to prevent or treat hepatocellular carcinoma (5).…”