Department of Immunology, Tufts University, Boston, MA, USA.
CardioVascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Nat Cardiovasc Res. 2024 Aug;3(8):970-986. doi: 10.1038/s44161-024-00507-y. Epub 2024 Jul 17.
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 IFNγCD8 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.
多柔比星是最常被开处的化疗药物，会引起剂量依赖性的心脏毒性和心力衰竭。然而，我们对多柔比星引起的免疫反应的理解是有限的。在这里，我们表明，多柔比星诱导的心脏损伤后异常的 CD8 T 细胞免疫反应会导致不良的重构和心肌病。在非肿瘤荷瘤小鼠中，多柔比星治疗会增加循环和心脏中的 IFNγCD8 T 细胞，并激活淋巴组织中的效应 CD8 T 细胞。此外，多柔比星促进心脏 CD8 T 细胞浸润，而在多柔比星治疗的小鼠中耗尽 CD8 T 细胞则会减少心脏纤维化并改善收缩功能。多柔比星处理诱导心脏成纤维细胞表达 ICAM-1，导致 CD8 T 细胞黏附和转化增强、接触依赖性 CD8 脱颗粒和颗粒酶 B 的释放。患有犬淋巴瘤和血液恶性肿瘤的患者在接受多柔比星治疗后会出现循环 CD8 T 细胞增加。在人类癌症患者中，T 细胞表达 IFNγ和 CXCR3，而 CXCR3 配体 CXCL9 和 CXCL10 的血浆水平与收缩功能下降相关。
