Ming-Ming Wu, Yu Sun, Yue Zhang, Yan-Chao Yang, Zhi-Xi He, Shuang Zhou, Xia Wang, Han Xiao, Miao Yu, Chang Miao, Bo-Wen Zhang, Xiao-Long Liu, Jie-Yu Chang, Di Zhu, Zi Hong, Mei Zhang, Hao-Tian Xu, Xin Bi, Song-Qi Han, Jian-Jun Mao, Jing Shi, Chen Liang, Qiu-Shi Wang, Qun Shao, Jun Zhang, Chang-Jiang Yu, Jian-Yu Liu, Xin-Hao Han, Tong Liu, Hai-Xia Liu, Lu-Yang Yu, Hai-Bo Jia, Yong Ji, Zhen-Wei Pan, Yue Li, Zhi-Ren Zhang
Anti-PD-1 antibody enhances myocardial infiltration of CXCR3+ CD8+ T cells under TAC condition through CXCL9/CXCL10-mediated chemotaxis. The increased granzyme B and perforin likely derived from CD8+ T cells impair function of mitochondrial respiratory chain complexes to cause cardiomyocyte apoptosis, thereby exacerbating TAC-induced cardiomyopathy and HF. CXCL9/CXCL10-CXCR3+ CD8+ T cell axis may represent a promising target for combating anti-PD-1 antibody-associated cardiotoxicity.
BACKGROUND: The use of anti-programmed cell death-1 (PD-1) antibody increases heart failure (HF) risk in patients with cancer with preexisting cardiovascular conditions. However, the underlying mechanism remains incompletely understood.
METHODS: To evaluate the effects of anti-PD-1 antibody on transverse aortic constriction (TAC)-induced cardiac remodeling and HF, anti-PD-1 antibody-treated mice; T cell-, myeloid-, and CD8+ T cell-specific Pdcd1 knockout; C-X-C motif chemokine receptor 3 (Cxcr3) knockout; and granzyme B (Gzmb) knockout mice combined with flow cytometry, Western blotting, immunofluorescence staining, pharmacological approaches, and bulk RNA-sequencing analyses were used.
RESULTS: Administration of anti-PD-1 antibody, T cell-, or CD8+ T cell-specific Pdcd1 deletion, but not myeloid-specific Pdcd1 knockout, aggravated TAC-induced cardiomyopathy and HF in mice. Mechanistically, PD-1 blockade or deletion increased myocardial infiltration of CXCR3+ CD8+ T cells, leading to granzyme B/perforin-mediated impairment of cardiomyocyte mitochondrial complex I to exacerbate TAC-induced cardiac injury and HF. TAC-enhanced chemotaxis, between cardiac fibroblast-derived CXCL9/CXCL10 and CXCR3+ CD8+ T cells, was a driving force for recruiting CXCR3+ CD8+ T cells under the conditions of PD-1 blockade or deletion. The worsened TAC-induced cardiomyopathy caused by anti-PD-1 antibody or T cell-specific Pdcd1 deletion was rescued by genetic deletion or pharmacological blockade of granzyme B and CXCR3.
CONCLUSIONS: Anti-PD-1 antibody enhances myocardial infiltration of CXCR3+ CD8+ T cells under TAC condition through CXCL9/CXCL10-mediated chemotaxis. The increased granzyme B and perforin likely derived from CD8+ T cells impair function of mitochondrial respiratory chain complexes to cause cardiomyocyte apoptosis, thereby exacerbating TAC-induced cardiomyopathy and HF. CXCL9/CXCL10-CXCR3+ CD8+ T cell axis may represent a promising target for combating anti-PD-1 antibody-associated cardiotoxicity.