Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by pathological epithelial remodeling and excessive extracellular matrix (ECM) deposition, with limited therapeutic options. In IPF lungs, a distinct KRT5−/KRT17+ aberrant basaloid cell population—localized at the periphery of myofibroblast foci—expresses basal epithelial and senescence markers, along with IPF-associated molecules such as αVβ6 integrin. These pathologic cells are capable of promoting fibroblast proliferation and collagen production. Thus, targeted elimination of KRT17+ aberrant basaloid cells may ameliorate pulmonary fibrosis. Methods We generated chimeric antigen receptor (CAR) T cells directed against integrin αVβ6 by transducing primary murine T cells with a lentiviral vector. CAR-T cell cytotoxicity was evaluated using a luciferase-based killing assay. Therapeutic efficacy was assessed in a bleomycin-induced murine model of pulmonary fibrosis. Results We developed an αVβ6-specific CAR-T cell that exhibited potent and specific cytolytic activity against αVβ6high target cells in vitro, with minimal impact on αVβ6low cells. In bleomycin-challenged mice, a single intravenous infusion of αVβ6 CAR-T cells significantly reduced lung collagen deposition and improved histological fibrosis scores compared to mice treated with control T cells. Following CAR-T cell administration, mice showed rapid recovery of body weight and lung coefficient, and achieved the highest survival rate among all bleomycin-exposed groups. Conclusion Our study establishes proof-of-concept that adoptive transfer of αVβ6-targeting CAR-T cells can selectively deplete a pro-fibrotic pathogenic cell subset, highlighting this approach as a promising and highly specific therapeutic strategy for IPF. This abstract is funded by: None
Chen et al. (Fri,) studied this question.