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

> **NIH NIH R03** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $123,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10598102
- **Project number:** 5R03DK132437-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Lily Dara
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $123,750
- **Award type:** 5
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598102

## Citation

> US National Institutes of Health, RePORTER application 10598102, Targeting Cell Death Pathways in Immune-mediated Liver Injury from Checkpoint Inhibitors (5R03DK132437-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10598102. Licensed CC0.

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