Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction.
Nat Cardiovasc Res
; 3(8): 970-986, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-39196030
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fibrose
/
Linfócitos T Citotóxicos
/
Doxorrubicina
/
Interferon gama
/
Modelos Animais de Doenças
Idioma:
En
Revista:
Nat Cardiovasc Res
/
Nat. cardiovasc. res
/
Nature cardiovascular research
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos