# Identification of Causal T-Cell Mechanisms in Immune Checkpoint Inhibitor Induced Myocarditis

> **NIH NIH K08** · STANFORD UNIVERSITY · 2023 · $48,393

## Abstract

PROJECT SUMMARY/ABSTRACT
 Myocarditis, pathologic inflammation of the heart, is a serious cause of sudden cardiac death affecting
patients of all age groups. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies to cytotoxic T-cell
antigen-4 (CTLA-4) or programmed death-1 (PD-1)/programmed death-1 ligand (PD-1L) used as novel cancer
therapeutics to release intrinsic brakes on T-cell cytotoxicity against tumor cells. Although ICIs are now relied
upon to treat many advanced cancers, fulminant myocarditis has been reported as a life-threatening side effect
of these drugs, leading to severe arrhythmias, heart failure and death. Under histopathology, an acute
lymphocytic infiltrate is found in the heart, and multiple lines of evidence point to a T-cell and antigen-mediated
phenomenon. In this proposal, Dr. Zhu’s preliminary data in ICI myocarditis patients and a germline PD-1
knockout mouse model of ICI myocarditis (MRL-Pdcd1-/-) demonstrates a population of clonally-expanded
cytotoxic effector CD8+ T-cells thought to play a critical role in this disease, with upregulation of the chemokine
RANTES (CCL5) and its receptor (CCR5). Dr. Zhu hypothesizes that ICI myocarditis is caused by the clonal
expansion of cytotoxic effector CD8+ T-cells in the heart, whose pathogenesis is potentiated by signaling from
CCL5, and she will aim to test this hypothesis using single-cell RNA-seq/single-cell TCR sequencing and T-cell
adoptive transfer experiments (Aim 1), as well as and ex-vivo/in-vivo knockdown of CCR5 in MRL-Pdcd1-/- mice
(Aim 2).
 Although T-cell clonal analysis of patient heart tissues suggest the existence of a cardiac-specific antigen
in ICI-induced myocarditis, the identity of such antigen(s) remains elusive. Understanding the culprit antigens in
this disease may lead to novel insights in T-cell mediated myocardial damage. In the second part of her proposal,
Dr. Zhu hypothesizes that ICI-induced myocarditis is an autoimmune disorder caused by cardiac-specific auto-
antigens that trigger the activation/clonal expansion of T-cells, leading to myocardial inflammation. In Aim 3,
she will utilize the novel computational algorithm called GLIPH (Grouping Lymphocyte Interactions by Paratope
Hotspots) to identify candidate pathogenic antigens in ICI myocarditis. Dr. Zhu’s work will bridge a major
knowledge gap in the field of cardiac inflammation and identify culprit T-cell subsets and disease-causing
antigens in ICI myocarditis and T-cell induced myocardial injury. The completion of this proposal will provide a
platform for Dr. Zhu’s successful transition to an independent physician scientist investigating immune
mechanisms in cardiac inflammation/toxicity.

## Key facts

- **NIH application ID:** 10712007
- **Project number:** 3K08HL161405-02S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Han Zhu
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $48,393
- **Award type:** 3
- **Project period:** 2022-01-15 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10712007

## Citation

> US National Institutes of Health, RePORTER application 10712007, Identification of Causal T-Cell Mechanisms in Immune Checkpoint Inhibitor Induced Myocarditis (3K08HL161405-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10712007. Licensed CC0.

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