IRF4: A potential prognostic biomarker for immunotherapy in NSCLC

Background: Immunotherapy is revolutionizing the management of advanced non-small cell lung cancer (NSCLC). However, sustained responses are observed in only a minority of patients. Reliable biomarkers are required to identify potential beneficiaries. Interferon regulatory factor 4 (IRF4) plays a crucial role in immune regulation, suggesting its potential as a prognostic biomarker in NSCLC immunotherapy. This study aimed to investigate the predictive role of IRF4 expression in patients with NSCLC receiving immunotherapy. Methods: Data from three NSCLC cohorts treated with immune checkpoint inhibitors were collected from the Gene Expression Omnibus (GEO) database. The prognostic significance of IRF4 was assessed across these cohorts, and gene set enrichment analysis (GSEA) was performed. IRF4-based nomograms were developed to predict the outcomes of immunotherapy. Correlations among IRF4 expression, immune cell infiltration, and immunotherapy prognosis were evaluated in our cohort. Results: Elevated IRF4 expression was associated with improved prognosis in patients with NSCLC undergoing immunotherapy, consistent with both GEO dataset and our cohort. IRF4 emerged as an independent predictor for progression-free survival (PFS) and overall survival (OS) in multivariable Cox regression analysis. GSEA analysis highlighted links between IRF4 expression and immune activation pathways such as Chemokine_Signaling_Pathway, Natural_Killer_Cell_Mediated_Cytotoxicity, B_Cell_Receptor_Signaling_Pathway, and T_Cell_Receptor_Signaling_Pathway. In our cohort, immunohistochemistry demonstrated correlations between IRF4 expression and the infiltration of CD8+ T cells, CD20+ B cells, and PD-L1 expression in the tumor microenvironment. Conclusion: High IRF4 expression in baseline tumor tissue could serve as a favorable predictor of NSCLC immunotherapy outcomes, aiding in personalized treatment strategies.