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  1. FDA STEM Outreach, Education and Engagement

Immune-mediated Liver Injury Caused by Immune Checkpoint Inhibitors Displays a High Immune Tolerance and Rigorous Hepatocyte Regeneration Phenotype

Authors:
Poster Author(s)
Zhu, Christina, FDA/CDER (Student); Fennell, Christie Jane, FDA/CDER (Fellow); Chi, Scherina, FDA/CDER (Student); Bacot, Silvia M., FDA/CDER (Mentor); Wang, Tao, FDA/CDER (Mentor); Yeh, Matthew M., University of Washington School of Medicine (Mentor); Feldman, Gerald M., FDA/CDER (Mentor)
Center:
Contributing Office
Center for Drug Evaluation and Research

Abstract

Poster Abstract

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment. However, many patients need to terminate therapy due to Immune-mediated Liver Injury Caused by Immune Checkpoint Inhibitors (ILICI) which is an immune-related adverse event (irAE). Currently, very few prognostic biomarkers have been identified with respect to ILICI because the mechanism for ICI induced hepatotoxicity is not fully understood. Previous studies have shown that the extent of liver regeneration is a major factor in determining the outcomes in patients with drug-induced liver toxicity (DILI). Studies from our lab and others have also demonstrated that the immune status of a patient is critical for drug induced hepatotoxicity. However, little is known about the status of immune activation, especially the association of activation of immune cells with liver regeneration in patients with ILICI. In this study, we assess the correlation between liver regeneration and immune activation status using immunohistochemistry (IHC) staining to examine the levels of Ki67, a proliferation marker, and CTLA-4, an immunosuppressive biomarker, in patients who developed ILICI. While Ki67 positive hepatocytes are present in liver tissue from patients with ILICI and DILI compared to liver tissue in healthy donors, the numbers of CTLA-4 positive T-cells and Kupffer cells are significantly higher in ILICI patients than in DILI patients. In contrast, healthy control patients exhibited few Ki67 positive cells and no CTLA-4 positive cells. Our results suggest that immune activation may play a critical role in drug-induced liver toxicity especially with regards to ILICI, and the assessment of the correlation between Ki67 and CTLA-4 may provide a new tool to predict the patient outcomes in response to ILICI.

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