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

Abstract

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. 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 <i>Pdcd1</i> knockout; C-X-C motif chemokine receptor 3 (<i>Cxcr3</i>) knockout; and granzyme B (<i>Gzmb</i>) knockout mice combined with flow cytometry, Western blotting, immunofluorescence staining, pharmacological approaches, and bulk RNA-sequencing analyses were used. Administration of anti-PD-1 antibody, T cell-, or CD8⁺ T cell-specific <i>Pdcd1</i> deletion, but not myeloid-specific <i>Pdcd1</i> 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 <i>Pdcd1</i> deletion was rescued by genetic deletion or pharmacological blockade of granzyme B and CXCR3. 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.