IFN-γ 介导的 Caspase-7 抑制加重 CAR-T 细胞诱导的急性肺损伤

On-target off-tumor effects precipitate severe adverse reactions in patients, significantly hindering the application of chimeric antigen receptor (CAR) T cells in both hematological and solid tumors. The underlying mechanisms remain elusive due to the absence of suitable preclinical models.

To elucidate these mechanisms, a human epidermal growth factor receptor 2 (Her2) transgenic mouse model was developed to investigate CAR-T cell-induced on-target off-tumor effects. CAR-T cells initially migrated to the lungs, targeting alveolar epithelial cells and resulting in interferon- (IFN- )-dependent acute lung injury.

Additionally, a regulatory mechanism involving IFN- -induced degradation of caspase-7 mRNA 5' untranslated regions (UTR), which amplifies acute lung injury mediated by CAR-T cells, was identified. Consequently, a strategy was validated to antagonize IFN- during CAR-T cell infusion, thereby mitigating acute lung injury without compromising antitumor efficacy.

These findings elucidate the mechanisms of CAR-T cell-induced acute lung injury and demonstrate the viability of targeting IFN- to prevent this adverse reaction.