Inhibition of Programmed Cell Death-1 in Cytotoxic CD8 + T Cells Exacerbates Pressure Overload–Induced Cardiac Injury

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.