Related Experiment Video
Updated: Apr 17, 2026
Exosomal miRNA Analysis in Non-small Cell Lung Cancer NSCLC Patients' Plasma Through qPCR: A Feasible Liquid Biopsy Tool
Published on: May 27, 2016
EGFR-Mutant Lung Adenocarcinoma Cell-Derived Exosomal miR-651-5p Induces CD8+ T Cell Apoptosis via Downregulating
Chao Zhao1, Lei Cheng1, Aiwu Li2
1Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
Abstract:
Background: The efficacy of programmed cell death 1 (PD-1) or ligand 1 (PD-L1) inhibitors in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients is not satisfactory. Studies have indicated that the ratio of CD8+ tumor infiltration lymphocytes (TILs) was associated with immunotherapy efficacy; however, it was significantly lower in EGFR-mutant than wild type patients. The underlying mechanisms need to be studied. Methods: Database analysis, clinical specimens, small RNA sequencing, and single-cell sequencing were used to analyze miRNA expression and immune cell infiltration. Cell co-culture and flow cytometry were conducted to detect immune cell apoptosis. The mouse model was performed to analyze the influence of miR-651-5p antagomirs on the tumor microenvironment. Results: The miR-651-5p was found to be highly expressed in EGFR-mutant lung adenocarcinoma cell-derived exosomes, which could promote CD8+ T cell apoptosis, while the miR-651-5p inhibitor decreased the ratio of PC9-secreted exosomes and induced apoptosis. Mechanistically, the EGFR signaling pathway promoted the expression of miR-651-5p by activating the transcription factor Fos proto-oncogene (FOS) in EGFR-mutant lung adenocarcinoma cell lines. B-cell lymphoma 2 (BCL2) was the target of miR-651-5p, and miR-651-5p could promote T cell apoptosis by inhibiting BCL2 expression. In addition, the miR-651-5p antagomir increased T cell infiltration and enhanced the efficacy of the PD-1 inhibitor treating the EGFR-mutant lung adenocarcinoma humanized mouse model. Conclusions: EGFR-mutant lung adenocarcinoma promotes T cell apoptosis through exosomal miR-651-5p. miR-651-5p antagonists increase immune cell infiltration and enhance the anti-tumor effect of PD-1 inhibitor, suggesting a new combination therapy to improve the efficacy of immunotherapy in EGFR-mutant NSCLC patients.
Insights
EGFR-mutant lung cancer hinders immunotherapy by promoting T cell death via exosomal miR-651-5p. Inhibiting miR-651-5p boosts T cell infiltration and PD-1 therapy effectiveness.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Programmed cell death 1 (PD-1) inhibitors show limited efficacy in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).
- CD8+ tumor-infiltrating lymphocytes (TILs) are crucial for immunotherapy response but are reduced in EGFR-mutant NSCLC.
- Understanding the mechanisms behind reduced TILs in EGFR-mutant NSCLC is critical for improving treatment outcomes.
Purpose of the Study:
- To investigate the role of microRNA (miRNA) in mediating immune evasion in EGFR-mutant lung adenocarcinoma.
- To elucidate the mechanism by which EGFR mutations influence T cell infiltration and apoptosis.
- To explore the potential of targeting exosomal miR-651-5p as a therapeutic strategy to enhance immunotherapy in EGFR-mutant NSCLC.
Main Methods:
- Analysis of miRNA expression and immune cell infiltration using database analysis, clinical specimens, small RNA sequencing, and single-cell sequencing.
- In vitro studies involving cell co-culture and flow cytometry to assess immune cell apoptosis.
- In vivo studies using a humanized mouse model to evaluate the therapeutic effect of miR-651-5p antagomirs in combination with PD-1 inhibitors.
Main Results:
- Exosomal miR-651-5p was significantly upregulated in EGFR-mutant lung adenocarcinoma and induced CD8+ T cell apoptosis.
- EGFR signaling pathway activation, via FOS, promoted miR-651-5p expression, which targets BCL2 to enhance T cell apoptosis.
- Administration of miR-651-5p antagomirs increased T cell infiltration and improved the anti-tumor efficacy of PD-1 inhibitors in a preclinical model.
Conclusions:
- EGFR-mutant lung adenocarcinoma suppresses anti-tumor immunity by increasing exosomal miR-651-5p, leading to T cell apoptosis.
- Targeting exosomal miR-651-5p with antagonists represents a promising strategy to enhance immune cell infiltration.
- Combination therapy with miR-651-5p antagonists and PD-1 inhibitors may overcome immunotherapy resistance in EGFR-mutant NSCLC patients.
Related Concept Videos
02:38Mitogens and the Cell Cycle
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
01:17The Extrinsic Apoptotic Pathway