1016O - Autoimmunity against surfactant protein B drives immune checkpoint inhibitor-related pneumonitis in patients with NSCLC

Background

Immune checkpoint inhibitor (ICI)-related pneumonitis is a common and serious immune-related adverse event (irAE) in patients with non-small cell lung cancer (NSCLC). The factors driving the development of ICI-related pneumonitis in some patients and not others are poorly understood.

Methods

A prospective cohort of patients with stage IV NSCLC and stage IV melanoma who received ICI treatment was established across four clinical centers in Switzerland. Patient blood was drawn pre-treatment, at every cycle of treatment and, where possible, at the time point of irAE onset. Lung tumor/pneumonitis biopsies were available from some patients. Serum samples were used to perform a high-throughput proteomics analysis as well as ELISAs. Biopsies were used to perform immunohistochemistry and mass spectrometry-based HLA immunopeptidomics analyses. PBMCs were isolated from blood and used to perform in vitro T cell stimulation assays followed by flow cytometric cell acquisition. Lastly, PBMCs were also used to perform cell sorting and single cell RNA sequencing.

Results

Using longitudinal samples from a prospective cohort of 144 ICI-treated patients with NSCLC we uncovered important differences between patients with pneumonitis and those without: pre-treatment, patients with pneumonitis showed significantly higher levels of IgG autoantibodies targeting surfactant protein B (SP-B); while, at the onset of pneumonitis, these patients exhibited significantly higher frequencies of CD4⁺ IFN-γ⁺ SP-B-specific T cells in their blood. At the onset of pneumonitis patients also expressed a distinct serum proteomic profile including well-known inflammation-associated immune mediators. Finally, they harbored higher frequencies of T cell clonotypes likely to recognize SP-B in their blood than control patients without pneumonitis.

Conclusions

Our data suggest that the co-occurrence of SP-B-specific IgG autoantibodies and SP-B-specific CD4⁺ T cells leads to the development of ICI-related pneumonitis in patients with NSCLC. Our data also indicate that the pre-treatment level of SP-B-specific IgG may be used as a potential biomarker to identify patients at higher risk of developing ICI-related pneumonitis.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Lungenliga St.Gallen Appenzell.

Disclosure

L. Flatz: Financial Interests, Personal, Stocks or ownership: Hookipa Pharma; Financial Interests, Personal, Invited Speaker: BMS, Novartis, Sanofi; Financial Interests, Personal, Advisory Board: BMS, Novartis, Sanofi; Financial Interests, Institutional, Research Funding: Hookipa Pharma; Financial Interests, Personal, Royalties: Hookipa Pharma; Financial Interests, Personal, Advisory Role: Philogen. M. Frueh: Financial Interests, Institutional, Advisory Role: BMS, AstraZeneca, MSD, Takeda, Roche, Lilly, Boehringer Ingelheim, Novartis, Amgen. C. Antonio: Financial Interests, Personal, Advisory Role: AbbVie, Sanofi, Eli Lilly, Philogen. H. Läubli: Financial Interests, Personal, Financially compensated role: Bristol Myers Squibb, Merck Sharp Dome, Roche, Novartis; Financial Interests, Personal, Member of Board of Directors: Singenavir Ltd; Financial Interests, Personal, Other: Palleon Pharmaceuticals, Glycoera. All other authors have declared no conflicts of interest.