Single-cell profiling unveils an exhaustion trajectory of ZNF683hi tissue-resident alveolar CD8+ T cells in checkpoint inhibitor pneumonitis

Background Checkpoint inhibitor pneumonitis (CIP) is the leading cause of treatment-related deaths for immune checkpoint inhibitor (ICI) combination therapies. CIP is problematic to diagnose and differentiate, particularly from radiation pneumonitis (RP), due to the lack of mechanistic distinctions between them. Methods Using single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq), we characterize the cellular landscape of bronchoalveolar lavage fluid (BALF) and peripheral blood from a discovery cohort (seven CIP, six RP, and six treatment-naive controls) and a validation cohort (five patients receiving combined ICI and radiotherapy who were diagnosed with RP). Findings We report a striking accumulation of alveolar CD8 + exhausted T cells (Texs) in CIP. The alveolar CD8 + Texs of CIP primarily differentiate from tissue-resident ZNF683 hi CD8 + T cells, whereas those of RP predominantly originate from peripherally related GZMK hi CD8 + T cells. These findings were further validated in a prospectively enrolled validation cohort and ultimately guided successful clinical decisions regarding ICI rechallenge. Conclusions These results highlight distinct cellular and molecular features in CIP and RP, thereby providing insights into clinical decision-making regarding ICI rechallenge in lung cancer patients. Funding This study was supported by the National Natural Science Foundation of China.