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Central memory CD4+ T cells play a protective role against immune checkpoint inhibitor-associated myocarditis

Jiajun Yu1,2, Bo Long3, Ziyong Li1,2

  • 1School of Medicine, Chongqing University, Chongqing 400030, China.

Cardiovascular Research
|June 8, 2024
PubMed

Insights

Immune checkpoint inhibitors (ICIs) can cause myocarditis. This study found that CD4+ TCM cells protect the heart during ICI therapy. Targeting IL-15, IL-4I1, and CD4+ TCM cells may prevent ICI-associated myocarditis.

Area of Science:

  • Immunology
  • Oncology
  • Cardiology

Background:

  • Immune checkpoint inhibitors (ICIs) improve cancer survival but can cause immune-related adverse events.
  • ICI-associated myocarditis is a rare but severe complication with high mortality.
  • Understanding the mechanisms of ICI-associated myocarditis is crucial for patient safety.

Purpose of the Study:

  • To investigate the immune cell subsets and inflammatory factors involved in ICI-associated myocarditis.
  • To elucidate the role of CD4+ T central memory (TCM) cells in cardiac protection during ICI therapy.
  • To identify potential therapeutic targets for preventing ICI-associated myocarditis.

Main Methods:

  • Analysis of peripheral blood immune cells and inflammatory factors in patients and mice undergoing ICI therapy.
  • RNA sequencing of CD4+ TCM cells to identify immunosuppressive factors.
  • Protein array analysis to assess inflammatory factor levels.
  • In vivo studies using anti-PDL1 antibody and IL-15 in a mouse tumor model.

Main Results:

  • ICI-associated myocarditis was linked to increased NK and myeloid cells, decreased T cells, and an imbalanced CD4/CD8 ratio, with reduced CD4+ TCM cells.
  • CD4+ TCM cells in myocarditis patients expressed the immunosuppressive factor IL-4I1.
  • Decreased IL-15 and increased inflammatory factors (IL-1B, CXCL13, CXCL9) correlated with myocarditis severity.
  • In mice, anti-PDL1 treatment reduced CD4+ TCM cells and increased cardiac fibrosis; IL-15 administration restored CD4+ TCM cells and mitigated fibrosis.

Conclusions:

  • CD4+ TCM cells play a critical role in cardiac protection during ICI therapy.
  • IL-15, IL-4I1, and CD4+ TCM cells are potential therapeutic targets for mitigating ICI-associated myocarditis.
  • Targeting these factors could improve the safety of ICI therapy for cancer patients.
Abstract

Keywords:
Central memory CD4ICI-associated myocarditisIL-15IL-4I1

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