Mechanisms of immune checkpoint inhibitor-mediated liver injury

Abstract

The immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1/ligand-1 (PD-1/PD-L1) are vital contributors to immune regulation and tolerance. Recently immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, they come with the cost of immune related adverse events involving multiple organs such as the liver. Due to its constant exposure to foreign antigens, the liver has evolved a high capacity for immune tolerance, therefore, blockade of the immune checkpoints can result in aberrant immune activation affecting the liver in up to 20% of patients depending on the agent(s) used and underlying factors. This type of hepatotoxicity is termed immune mediated liver injury from checkpoint inhibitors (ILICI) and is more common when CTLA4 and PD-1/PD-L1 are used in combination. The underlying mechanisms of this unique type of hepatotoxicity are not fully understood; however, the contribution of CD8⁺ cytotoxic T lymphocytes, various CD4⁺ T cells populations, cytokines, and the secondary activation of the innate immune system leading to liver injury have all been suggested. This review summarizes our current understanding of the underlying mechanisms of liver injury in immunotherapy using animal models of ILICI and available patient data from clinical studies.

Keywords: Apoptosis; CTLA-4; Cell death; DILI; Hepatocyte; Hepatotoxicity; Immunotherapy; Necrosis; PD-1; PD-L1.

Graphical abstract

Figure 1

Immune checkpoint inhibitors, site of action. Antigen presentation by major histocompatibility complex (MHC) class II molecules on antigen presenting cells (APCs) leads to antigen recognition by the T cell receptor (TCR) and T cell activation. B7-1/2 binding to CD28 surface receptor further modulates T cell activation signals. CTLA-4 located on the T cell surface competes for CD28 receptor binding to block T cell activation. CTLA-4 inhibitors, ipilimumab, and tremelimumab interfere with this interplay and promote T-cell activation. PD-1/PD-L1 interactions have been shown to diminish the activity of mature T cells after T cell receptor signaling has been initiated. PD-1 and PD-L1 inhibitors such as pembrolizumab, nivolumab, cemiplimab, pidilizumab, avelumab, atezolizumab and durvalumab function by blocking the PD-1/PD-L1 interaction thereby promoting T-cell activation and survival. APC, antigen presenting cells; CTLA-4, The cytotoxic T-lymphocyte-associated antigen-4; MHC, major histocompatibility complex; PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein ligand 1; TCR, T cell receptor.

Figure 2

Immune tolerance in the liver. Several mechanisms and types of cells contribute to the tolerogenic environment in the liver. (A) Constant low dose exposure to pathogen associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) from the intestine prime the liver cell population and promote an immunotolerant microenvironment. LPS promotes a state of immune tolerance by affecting the secretion on IL-10, IL-27 and TGF-β by multiple cells including dendritic cell (DCs), liver sinusoidal endothelial cells (LSECs), and Kupffer cells (KC). LSECs secrete anti-inflammatory cytokines and promote Th0 phenotype and FOXP3 Tregs. They activate naïve CD4⁺ T cells which also secrete IL-10. Non-parenchymal liver cells have been shown to express PD-L1. Hepatocytes also participate in immune tolerance, although the level of PD-L1 expression on healthy and unstimulated liver parenchymal cells is controversial. (B) Another mechanism of immune tolerance induction is suppression of CD8⁺ CTLs. Hepatocytes can act as APCs and activate naïve CD8⁺ T cells that ultimately undergo apoptosis and clonal deletion due to lack of sufficient co-stimulation. PD-L1 expression on liver non-parenchymal cells is critical for induction of CD8⁺ T cell apoptosis. KCs, LSECs, and hepatic stellate cells (HSCs) increase CD4⁺ regulatory T cells (Tregs) suppressive activity and cause clonal deletion of cytotoxic T lymphocytes (CTLs) by apoptosis. CTLA-4 expression on CD4⁺ Tregs contributes to maintenance of liver immune tolerance by downregulating CD8⁺ CTLs. APC, antigen presenting cell; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T lymphocyte associated antigen 4; DC, dendritic cell; FOXP3, forkhead box P3; HSC, hepatic stellate cells; IL-10, interleukin 10; IL-27, interleukin 27; KC, Kupffer cell; LPS, lipopolysaccharide; LSEC, liver sinusoidal endothelial cell; PAMPs, pathogen associated molecular patterns; PD-L1, programmed cell death protein ligand 1; Treg, regulatory T cell; TGF-β, transforming growth factor beta.