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SERPINA3 as a Secreted-Protein Biomarker Associated with Poor Prognosis and T-Cell Dysfunction in Non-small Cell Lung
Joon Kim1,2, Geunin Lee1, Seung-Hyun Yong1
1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Background:
Lung cancer remains the leading cause of cancer-related mortality, with poor outcomes driven by late presentation and therapy resistance. While genes encoding secreted proteins may reflect tumor biology and have biomarker potential, systematic multi-cohort studies that identify and validate prognostically relevant secreted protein candidates in non-small cell lung cancer (NSCLC) are limited.
Methods:
We conducted a multi-cohort transcriptomic screen of 1,896 genes encoding secreted proteins to nominate prognostic candidates in NSCLC. Candidates were prioritized based on differential expression between tumor and normal tissues and survival associations across public NSCLC cohorts. Serpin family A member 3 (SERPINA3) was selected for further validation in The Cancer Genome Atlas (TCGA) NSCLC dataset. Tumors were stratified by SERPINA3 expression for Kaplan-Meier survival analysis and gene set enrichment analysis (GSEA) using the Hallmark and Kyoto Encyclopedia of Genes and Genomes (KEGG) collections. Translational relevance was assessed in a retrospective bronchoalveolar lavage fluid (BALF) registry using multivariable Cox models.
Results:
In the TCGA NSCLC dataset, SERPINA3-high tumors had shorter overall survival (OS; log-rank p=0.016) and progression-free survival (PFS; log-rank p=0.018). GSEA showed enrichment in tumor necrosis factor-α/nuclear factor-κB, inflammatory response, interleukin 6 (IL-6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3), and IL-17 signaling pathways. The SERPINA3-high state exhibited a T-cell-infiltrated, checkpoint-high phenotype consistent with T-cell dysfunction, characterized by increased levels of transforming growth factor-β, IL-10, and indoleamine 2,3-dioxygenase (IDO). In the BALF registry, higher BALF-but not plasma-SERPINA3 independently predicted shorter PFS, with a nonsignificant trend toward OS after adjustment.
Conclusion:
Across datasets, SERPINA3 indicates an immune-inflammatory tumor state associated with worse survival. BALF-based measurement captured tumor-proximal signals that may be less apparent in plasma, supporting its potential clinical utility for risk stratification and warranting prospective validation.