CD248-targeted BBIR-T cell therapy against late-activated fibroblasts in cardiac repair after myocardial infarction
Haiting Chen, Ke Hu, Qi Tang, Junzhuo Wang, Qianyu Gu, Jiayu Chen, Jiaxin Hu, Ningxin Peng, Meng Guo, Yaohui Jiang, Qingbo Xu, Jun Xie
Abstract
Excessive cardiac fibrosis is a key cause of heart failure and adverse ventricular remodeling after myocardial infarction. The abnormally activated fibroblasts after scar maturation are the chief culprit. Single-cell RNA sequencing of mouse cardiac interstitial cells after myocardial infarction depicts a late-activated fibroblast subpopulation F-Act and initially identifies its characteristic antigen CD248, which is also verified in human hearts. On this basis, we develop a CD248-targeted biotin-binding immune receptor T cell therapy against F-Act to correct cardiac repair disorders. In our study, the precise removal of F-Act after the scar matured effectively inhibits fibrotic expansion in the peri-infarct zone and improves cardiac function. This therapy provides an idea for the treatment of cardiac fibrosis and also promotes the application of engineered T cells to non-tumor diseases. Abnormal activation of fibroblasts in mature scars after myocardial infarction is a key etiological factor in tissue repair disorders. Here, the authors developed a BBIR-T cell therapy that precisely targets pathogenic fibroblast subpopulations, thereby delaying ventricular remodeling and deterioration of cardiac function.