Mechanism of RBM15 in the Immune Escape of Non-small Cell Lung Cancer Cells Via the LncRNA EGFR-AS1/USP3/PD-L1 Axis.

Abstract

Non-small cell lung cancer (NSCLC) is the most prevalent subtype of lung cancer, with persistently low overall cure and survival rates, largely attributed to tumor immune escape. This study aims to explore the role of RBM15 in the immune escape of NSCLC and provide a potential therapeutic target. Firstly, RBM15, LncRNA EGFR-AS1, PCBP2, USP3, and PD-L1 were detected in NSCLC cells. Peripheral blood mononuclear cells (PBMCs) were co-cultured with NSCLC cells to assess PBMC cytotoxicity, CD8⁺T and CD107a+CD8+T cell proportion, and levels of IFN-γ, IL-10, and IL-2. To verify the mechanism, m6A enrichment on EGFR-AS1 was analyzed. The m6A modification sites on EGFR-AS1 were assayed. The interactions among EGFR-AS1-PCBP2, PCBP2-USP3, and USP3-PD-L1 were detected. We found that RBM15, EGFR-AS1 and PCBP2 were upregulated in NSCLC cells. Mechanistically, RBM15 stabilized EGFR-AS1 through m6A modification, increased the binding of EGFR-AS1 to PCBP2, and promoted USP3 expression. USP3 bound to PD-L1 and inhibited PD-L1 ubiquitination and degradation. In PBMC-NSCLC co-cultures, RBM15 downregulation increased PBMC cytotoxicity, CD8⁺T cell proportion, IFN-γ/IL-2 levels, and decreased IL-10 levels—effects partially reversed by EGFR-AS1 or USP3 overexpression. In conclusion, RBM15 enhances the immune escape of NSCLC through the EGFR-AS1/USP3/PD-L1 axis via m6A modification.