The miR-23a/27a/24-2 cluster drives immune evasion and resistance to PD- 1/PD-L1 blockade in non-small cell lung cancer

Programmed cell death protein ligand-1 (PD-L1) and major histocompatibility complex Ⅰ (MHC-Ⅰ) are key molecules related to tumor immune evasion and resistance to programmed cell death protein 1 (PD-1)/PD-L1 blockade. Here, we demonstrated that upregulation of all miRNAs in miR-23a/27a/24 − 2 cluster correlated with poor survival, immune evasion and PD-1/PD-L1 blockade resistance in non-small cell lung cancer (NSCLC). Overexpression all miRNAs in miR-23a/27a/24 − 2 cluster upregulated PD-L1 by targeting Cbl proto-oncogene B and downregulated MHC-Ⅰ through increasing eukaryotic initiation factor 3B (eIF3B) by targeting microphthalmia associated transcription factor. In addition, we demonstrated that miR-23a/27a/24 − 2 cluster miRNAs maintain its expression in NSCLC through increasing Wnt/β-catenin signaling regulated interaction of transcription factor 4 (TCF4) and miR-23a/27a/24 − 2 cluster promoter. Notably, pharmacologic targeting eIF3B pathway dramatically enhanced PD-1/PD-L1 blockade sensitivity in miRNAs of miR-23a/27a/24 − 2 cluster high expressing NSCLC by upregulating MHC-Ⅰ expression and keeping miR-23a/27a/24 − 2 cluster-induced high expression of PD-L1. In summary, we elucidate the mechanism by which miR-23a/27a/24 − 2 cluster miRNAs maintain its own expression and the molecular mechanism by which miR-23a/27a/24 − 2 cluster miRNAs promote tumor immune evasion and PD-1/PD-L1 blockade resistance. In addition, we provide a novel strategy for treatment of miR-23a/27a/24 − 2 cluster high expressing NSCLC.