Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade
American Journal of Respiratory and Critical Care Medicine, 2024
Wyss N., Berner F., Walter V., Jochum A., Purde M., Abdou M., Sinnberg T., Hofmeister K., Pop O., Hasan Ali O., Bauer J., Cheng H., Lütge M., Klümper N., Diem S., Kosaloglu-Yalcin Z., Zhang Y., Sellmer L., Macek B., Karbach J., König D., Läubli H., Zender L., Meyer B., Driessen C., Schürch C., Jochum W., Amaral T., Heinzerling L., Cozzio A., Hegazy A., Schneider T., Brutsche M., Sette A., Lenz T., Walz J., Rammensee H., Früh M., Jäger E., Becher B., Tufman A., Nuñez N., Joerger M., Flatz L.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Immunotherapy | Pathophysiology Patient Stratification | Serum |  Olink Target 96 |
Abstract
Rationale: Immune checkpoint inhibitor-related pneumonitis is a serious autoimmune event affecting up to 20% of patients with non-small cell lung cancer, yet the factors underpinning its development in some patients and not others are poorly understood. Objectives: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. Methods: The study cohort consisted of non-small cell lung cancer patients who gave blood samples before and during immune checkpoint inhibitor 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 non-small cell lung cancer and patients with melanoma. Measurements and Main Results: Across both cohorts, patients who developed pneumonitis had higher pre-treatment levels of immunoglobulin G autoantibodies targeting surfactant protein-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ interferon-gamma-positive surfactant protein B-specific T cells, and expanding T cell clonotypes recognizing this protein, accompanied by a pro-inflammatory serum proteomic profile. Conclusions: Our data suggest that the co-occurrence of surfactant protein-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pre-treatment levels of these antibodies may represent a potential biomarker for elevated risk of developing pneumonitis and on-treatment levels may provide a diagnostic aid.