Anti-PD1 therapy using nivolumab reduced cardiac fibrosis and increased cardiac function following myocardial infarction in mouse and non-human primate models.
Does PD-1 inhibition prevent cardiac fibrosis and improve cardiac function in myocardial infarction models?
PD-1 inhibition prevents post-MI cardiac fibrosis and improves cardiac function in preclinical models, highlighting a novel immunotherapeutic target for post-MI remodeling.
Abstract Background and Aims Myocardial fibrosis is a common pathological feature that affects the outcome of various heart diseases, typically in the condition of myocardial infarction (MI), and hence the extent of fibrosis becomes a major risk factor for predicting the prognosis of heart failure. On the other hand, while the roles of T cells in heart failure have been increasingly recognized, however, it remains not fully known whether PD1+ T cells modulate the cardiac fibrosis during the post-MI pathological remodeling process. Methods Single cell RNA sequencing and mass cytometry were conducted to identify the proportion of PD1+ T cells both in human ischemic diseases and mouse MI model. Bulk RNA sequencing and cytokine array were utilized to investigate the function of PD1+ T cells. Cardiac function and histology analysis were evaluated in non-human primates and rodents post MI. Results We observed significantly increased PD1+ T cells in the MI heart, the amount of which was positively associated with cardiac fibroblast activation and hence collagen secretion. Unlike in tumor, PD1+ T cells in MI heart demonstrated activated characteristics. PD-1 knockout (PD1-/-) mice exhibited reduced cardiac fibrosis, resulting in an increase in cardiac performance following MI. Mechanistically, the activated PD1+ T cells were shown to induce fibrosis via modulating the CXCL9/CXCR3 axis via interacting with cardiac fibroblasts, and this was independent of PD1/PD-L1 pathway. Importantly, the anti-PD1 therapy by novolumab administration in both mouse and non-human primate (NHP) MI models exerted the anti-fibrosis effects and resulted in increased cardiac function, without any noticeable side effects on other organ-tissues including the liver, the kidney and the thyroid. Conclusion The present study revealed the pro-fibrotic role of PD1+ T cells during the post-MI cardiac remodeling process, which was independent of its correlation with PD-L1. Our data strongly supported that PD-1 inhibition can serve as an effective immunotherapy for preventing post-MI cardiac fibrosis.
Hu et al. (Sat,) conducted a other in Myocardial infarction. Anti-PD1 therapy (nivolumab) was evaluated on Cardiac fibrosis and cardiac function. Anti-PD1 therapy using nivolumab reduced cardiac fibrosis and increased cardiac function following myocardial infarction in mouse and non-human primate models.