Increased PD-1 expression in livers associated with PD-1-antibody-induced hepatotoxicity

Area of Science:

• Immunology
• Hepatology
• Oncology

Background:

• Vanishing bile duct syndrome (VBDS) is a severe drug-induced liver injury characterized by chronic cholestasis and bile duct loss.
• VBDS has been observed following checkpoint inhibitor (ICI) therapy.
• Understanding the immune mechanisms underlying ICI-induced liver injury is crucial.

Purpose of the Study:

• To compare immune cell infiltrates in liver biopsies of patients with VBDS or hepatotoxicity after ICI treatment.
• To investigate the expression of PD-1 and PD-L1 in ICI-induced liver injury.
• To assess the direct effect of pembrolizumab on intrahepatic biliary epithelial cells.

Main Methods:

• Analysis of liver biopsies for CD3+, CD4+, CD8+, CD20+, CD57+, PD-1+, and PD-L1+ lymphocyte infiltrates.
• Comparison of ICI-treated patients (VBDS or hepatotoxicity) with control groups (normal liver, NASH, PBC, and ICI-treated without adverse events).
• In vitro study of pembrolizumab's effect on primary human intrahepatic biliary epithelial cells (HIBEpiC).

Main Results:

• ICI-treated patients showed significantly higher CD3+, PD-L1+, CD4+, and CD8+ infiltration compared to normal livers and other groups.
• PD-1+ infiltration was significantly increased in patients with severe hepatic adverse events.
• CD57+ infiltration was markedly elevated in ICI-treated patients compared to normal livers, NASH, and PBC groups.
• In vitro, pembrolizumab did not affect HIBEpiC viability despite PD-L1 expression.

Conclusions:

• VBDS induced by checkpoint inhibitors is not caused by direct cytotoxicity of the drugs.
• The immune response in ICI-induced liver injury differs from other cholestatic liver conditions.
• Upregulation of PD-1, PD-L1, and CD57+ cells in non-cancerous liver tissue may be associated with ICI-induced hepatotoxicity.