Bispecific Targeting of CHI3L1 and PD-1/PD-L1 Axis as a Novel Therapeutic Strategy for Idiopathic Pulmonary Fibrosis

Abstract

CHI3L1, a chitinase-like protein, plays a key role in the pathogenesis of pulmonary fibrosis, though the precise mechanisms remain unclear. This study explores how CHI3L1 regulates profibrotic macrophage activation and invasive myofibroblast differentiation and their interactions. In vitro, CHI3L1 induced profibrotic M2 macrophage activation and differentiation marked by increased expression of CD163, CD206, and PD-L1. CHI3L1 also enhanced TGF-{beta}1 effects on lung fibroblasts including myofibroblast transformation, migration and tissue invasion. Mechanistically, CHI3L1 increased TGF-{beta}1-stimulation of Smad, Akt and Erk signaling and PD-L1 played a significant role in TGF-{beta}1/CHI3L1-stimulated myofibroblast transformation. Coculture experiment further confirmed the ability of CHI3L1 to induce profibrotic macrophage activation that enhanced myofibroblast transformation mediated via a CD44-PD-L1 axis. Following in vivo bleomycin challenge, CHI3L1 transgenic mice exhibited significantly higher levels of PD-L1+ M2 macrophages, PD-L1+/PDGFR+ fibroblasts and increased numbers of PD-1+ and CD45+/PD-1+ cells compared to wild-type controls. Notably, combined treatment with anti-CHI3L1 and anti-PD-1 antibodies, or a bispecific anti-CHI3L1-anti-PD-1 antibody, resulted in greater inhibition of bleomycin-induced fibrosis than either antibody alone. These findings suggest that there is a stimulatory interaction between CHI3L1 and the PD-1/PD-L1 axis in promoting profibrotic macrophage activation and invasive fibroblast differentiation. The results also highlight the potential of bispecific targeting of CHI3L1 and the PD-1/PD-L1 pathway as an effective therapeutic approach for pulmonary fibrosis.