Upregulation of an Epithelial miRNA Is Associated with Immune Evasion in Progressive Bronchial Premalignant Lesions

Bronchial premalignant lesions (PML), precursors of lung squamous cell carcinoma, have distinct molecular subtypes. The proliferative subtype, enriched with bronchial dysplasia, had decreased expression of an antigen-processing/presentation gene coexpression module in progressive/persistent versus regressive PMLs, suggesting a functional impact of these genes on immune evasion. In this study, we performed miRNA sequencing, miRNA in situ hybridization, and spatial proteomics of bronchial biopsies from patients at high risk for lung cancer. An miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of the antigen presentation gene module. Staining on adjacent biopsy tissue showed that hsa-miR-149-5p was predominantly expressed in the epithelium and upregulated in progressive/persistent proliferative lesions. Targets of this miRNA, the transcriptional coactivator of MHC-I gene expression, NLRC5, and the genes it regulates, were downregulated in these lesions. Decreased NLRC5 expression reduced both IFNγ-induced MHC-I surface expression and CD8 T-cell cytotoxicity in lung squamous cancer cells. In PMLs, basal cells with high levels of NLRC5 were in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in vivo. These findings indicate a functional role for hsa-miR-149-5p in PML progression/persistence and suggest this axis as a potential therapeutic target for PML immunomodulation.