Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction

Nat Cardiovasc Res. 2024 Aug;3(8):970-986. doi: 10.1038/s44161-024-00507-y. Epub 2024 Jul 17.

Abstract

Doxorubicin, the most prescribed chemotherapeutic drug, causes dose-dependent cardiotoxicity and heart failure. However, our understanding of the immune response elicited by doxorubicin is limited. Here we show that an aberrant CD8+ T cell immune response following doxorubicin-induced cardiac injury drives adverse remodeling and cardiomyopathy. Doxorubicin treatment in non-tumor-bearing mice increased circulating and cardiac IFNγ+CD8+ T cells and activated effector CD8+ T cells in lymphoid tissues. Moreover, doxorubicin promoted cardiac CD8+ T cell infiltration and depletion of CD8+ T cells in doxorubicin-treated mice decreased cardiac fibrosis and improved systolic function. Doxorubicin treatment induced ICAM-1 expression by cardiac fibroblasts resulting in enhanced CD8+ T cell adhesion and transformation, contact-dependent CD8+ degranulation and release of granzyme B. Canine lymphoma patients and human patients with hematopoietic malignancies showed increased circulating CD8+ T cells after doxorubicin treatment. In human cancer patients, T cells expressed IFNγ and CXCR3, and plasma levels of the CXCR3 ligands CXCL9 and CXCL10 correlated with decreased systolic function.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / toxicity
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / immunology
  • Cardiomyopathies / pathology
  • Cardiotoxicity / etiology
  • Cell Adhesion / drug effects
  • Cell Degranulation / drug effects
  • Cells, Cultured
  • Chemokine CXCL10 / metabolism
  • Chemokine CXCL9 / metabolism
  • Disease Models, Animal*
  • Dogs
  • Doxorubicin* / adverse effects
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis* / chemically induced
  • Granzymes / metabolism
  • Humans
  • Interferon-gamma* / metabolism
  • Lymphocyte Activation / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / immunology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Receptors, CXCR3 / metabolism
  • Systole / drug effects
  • T-Lymphocytes, Cytotoxic* / drug effects
  • T-Lymphocytes, Cytotoxic* / immunology
  • Ventricular Function, Left / drug effects

Substances

  • Doxorubicin
  • Interferon-gamma
  • Antibiotics, Antineoplastic
  • Receptors, CXCR3
  • Chemokine CXCL10
  • Granzymes
  • CXCR3 protein, human
  • Gzmb protein, mouse
  • Chemokine CXCL9
  • IFNG protein, mouse
  • CXCL10 protein, human
  • IFNG protein, human