Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade.

Immune checkpoint inhibitor (ICI)-related pneumonitis is a serious autoimmune event affecting as many as 20% of patients with non-small-cell lung cancer (NSCLC), yet the factors underpinning its development in some patients and not others are poorly understood. To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. The study cohort consisted of patients with NSCLC who provided blood samples before and during ICI treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T-cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with NSCLC and patients with melanoma. Across both cohorts, patients in whom pneumonitis developed had higher pretreatment levels of immunoglobulin G autoantibodies targeting surfactant protein (SP)-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4 IFN-γ-positive SP-B-specific T cells and expanding T-cell clonotypes recognizing this protein, accompanied by a proinflammatory serum proteomic profile. Our data suggest that the cooccurrence of SP-B-specific immunoglobulin G autoantibodies and CD4 T cells is associated with the development of pneumonitis during ICI therapy. Pretreatment levels of these antibodies may represent a potential biomarker for an increased risk of developing pneumonitis, and on-treatment levels may provide a diagnostic aid.