Blocking CTLA‐4 promotes pressure overload‐induced heart failure via activating Th17 cells

Abstract

AbstractTargeting cytotoxic T‐lymphocyte‐associated antigen‐4 (CTLA‐4) with specific antibody offers long‐term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti‐CTLA‐4 antibody in pressure overload‐induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti‐CTLA‐4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti‐CTLA‐4 antibody exacerbated TAC‐induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti‐CTLA‐4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC‐treated mice. Importantly, anti‐CTLA‐4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin‐17A (IL‐17A) by an anti‐IL‐17A antibody. Furthermore, the C‐X‐C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti‐CTLA‐4‐mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti‐CTLA‐4 antibody exacerbates pressure overload‐induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL‐17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors‐induced cardiotoxicity.