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

• Published in: Molecular cancer 2024-12, Vol.23 (1), p.285-15, Article 285
• Main Authors: Luo, Hao, Hu, Bin, Gu, Xiang-Rong, Chen, Jing, Fan, Xiao-Qing, Zhang, Wei, Wang, Ren-Tao, He, Xian-Dong, Guo, Wei, Dai, Nan, Jian, Dan, Li, Qing, Xu, Cheng-Xiong, Jin, Hua
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immune Evasion; Lung cancer, Non-small cell; Lung cancer, Small cell; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; MicroRNA; MicroRNAs - genetics; Multigene Family; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Proto-Oncogene Mas; Tumor Escape - genetics
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-024-02201-w

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 the upregulation of all miRNAs in the miR-23a/27a/24 - 2 cluster was correlated with poor survival, immune evasion and PD-1/PD-L1 blockade resistance in patients with non-small cell lung cancer (NSCLC). The overexpression of all miRNAs in the miR-23a/27a/24 - 2 cluster upregulated PD-L1 expression by targeting Cbl proto-oncogene B (CBLB) and downregulated MHC-I expression by increasing the level of eukaryotic initiation factor 3B (eIF3B) via the targeting of microphthalmia-associated transcription factor (MITF). In addition, we demonstrated that the expression of the miR-23a/27a/24 - 2 cluster of miRNAs is maintained in NSCLC through increased Wnt/β-catenin signaling-regulated interaction of transcription factor 4 (TCF4) and the miR-23a/27a/24 - 2 cluster promoter. Notably, pharmacologic targeting of the eIF3B pathway dramatically increased sensitivity to PD-1/PD-L1 blockade in patients with high expression of the miR-23a/27a/24 - 2 cluster in NSCLC. This effect was achieved by increasing MHC-I expression while maintaining high expression of PD-L1 induced by the miR-23a/27a/24 - 2 cluster. In summary, we elucidate the mechanism by which the miR-23a/27a/24 - 2 cluster miRNAs maintain their own expression and the molecular mechanism by which the 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 the treatment of NSCLC expressing high levels of the miR-23a/27a/24 - 2 cluster.