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The miR-23a/27a/24 - 2 cluster drives immune evasion and resistance to PD-1/PD-L1 blockade in non-small cell lung
Hao Luo1,2, Bin Hu3, Xiang-Rong Gu4
1Department of Thoracic Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China.
Abstract:
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.
Insights
High levels of miR-23a/27a/24-2 cluster miRNAs in non-small cell lung cancer (NSCLC) promote immune evasion and resistance to PD-1/PD-L1 blockade by downregulating MHC-I and upregulating PD-L1. Targeting the eIF3B pathway can restore sensitivity to immunotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Programmed cell death protein ligand-1 (PD-L1) and major histocompatibility complex I (MHC-I) are crucial in tumor immune evasion and resistance to PD-1/PD-L1 blockade.
- The miR-23a/27a/24-2 cluster's role in non-small cell lung cancer (NSCLC) immune evasion and therapy resistance requires elucidation.
Purpose of the Study:
- To investigate the role of the miR-23a/27a/24-2 cluster in NSCLC immune evasion and resistance to PD-1/PD-L1 blockade.
- To elucidate the molecular mechanisms by which this miRNA cluster influences PD-L1 and MHC-I expression.
- To identify therapeutic strategies targeting the miR-23a/27a/24-2 cluster in NSCLC.
Main Methods:
- Correlation analysis of miRNA cluster expression with patient survival and immune evasion markers.
- Investigation of miRNA targeting of Cbl proto-oncogene B (CBLB) and microphthalmia-associated transcription factor (MITF).
- Assessment of Wnt/β-catenin signaling in regulating miRNA cluster expression.
- Evaluation of pharmacologic targeting of the eukaryotic initiation factor 3B (eIF3B) pathway in NSCLC models.
Main Results:
- Upregulation of the miR-23a/27a/24-2 cluster correlated with poor survival, immune evasion, and PD-1/PD-L1 blockade resistance in NSCLC patients.
- The miRNA cluster upregulated PD-L1 by targeting CBLB and downregulated MHC-I by increasing eIF3B via MITF.
- Wnt/β-catenin signaling maintained miR-23a/27a/24-2 cluster expression through TCF4 interaction.
- Targeting the eIF3B pathway increased sensitivity to PD-1/PD-L1 blockade by enhancing MHC-I expression while maintaining PD-L1 levels.
Conclusions:
- The miR-23a/27a/24-2 cluster plays a significant role in NSCLC immune evasion and PD-1/PD-L1 blockade resistance.
- Understanding the regulatory mechanisms of this miRNA cluster provides insights into tumor immune escape.
- Pharmacologic targeting of the eIF3B pathway presents a novel therapeutic strategy for NSCLC patients with high miR-23a/27a/24-2 cluster expression.
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