Immunopeptidome profiling in pulmonary fibrosis provides a platform for identifying therapeutic targets

Fibrosis is a severe pathological outcome of many chronic diseases, yet the therapeutic potential of targeting the altered major histocompatibility complex (MHC) class I immunopeptidome remains largely unexplored. Here we characterized the MHC class I immunopeptidomes from both fibrotic foci of human idiopathic pulmonary fibrosis lung explants and bleomycin-treated mice, identifying a diverse repertoire of fibrosis-associated peptides.

Parallel profiling of bleomycin-induced pulmonary fibrosis in mice enabled the computational prioritization of therapeutic targets. In vivo, therapeutic vaccination with three candidate peptides (MAF 116–124 , APBB2 70–78 and TNS3 119–127 ) effectively mitigated fibrosis progression in bleomycin-treated mice.

Furthermore, leveraging its evolutionary conservation, we found that MAF 116–124 elicited specific human cytotoxic T lymphocytes that lysed human idiopathic pulmonary fibrosis-derived myofibroblasts and M2-like macrophages. This study indicates that immunopeptidome profiling provides a robust platform for discovering translatable antifibrotic immunotherapies.

Fibrosis represents a common endpoint of diverse diseases, including idiopathic pulmonary fibrosis (IPF), viral hepatitis, metabolic dysfunction-associated steatohepatitis, chronic kidney disease and myocardial infarction 1 .