Targeting Cell Death Pathways in Immune-mediated Liver Injury from Checkpoint Inhibitors

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Project Summary Immune checkpoints are a normal part of the immune system that prevent T cells from autoreactivity. Cancer cells develop ways of evading clearance from cytotoxic T Cells by overexpressing these immune checkpoints. Immune Checkpoint Inhibitors (ICI) are antibodies that augment anti-tumor responses and restore tumor surveillance and clearance. One such drug acts against a checkpoint protein called cytotoxic T-lymphocyte- associated protein 4 (CTLA-4), while other immune checkpoint inhibitors target programmed death-1 (PD-1) and its ligand (PD-L1). Cancer immunotherapy has resulted in dramatically increased life expectancy from certain solid tumors. However, ICIs have serious immune related adverse effects including hepatotoxicity and liver injury, especially when combination CTLA4 and PD-L1 inhibitors are used. When Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI) is severe, immunotherapy must be discontinued. The Overall goal of this application is to investigate the mechanism of ILICI and ultimately design targeted solutions for mitigating this form of hepatotoxicity. How liver cells are targeted by the ICIs, which cells are the effectors of cell death, which cell death pathways are participating, and whether one cell death mode is dominant has not been studied. In this proposal, we describe a mouse model of ILICI and we propose to study the underlying cell death pathway leading to liver injury. By understating how liver injury occurs and how liver cells die, we plan to design targeted therapies to the liver to prevent and treat hepatotoxicity, enabling the continuation of lifesaving immunotherapy.