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Published on: March 30, 2019
Aerosolized miR-138-5p and miR-200c targets PD-L1 for lung cancer prevention
Qi Zhang1, Jing Pan1, Donghai Xiong1
1Center for Cancer Prevention, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, United States.
Abstract:
The development of chemopreventive strategies with the ability to prevent the progression of lung lesions to malignant cancers would reduce the mortality and morbidity resulting from this deadly disease. Delivery of microRNA (miRNA) by inhalation is a novel method for lung cancer prevention. In this study, we investigated the combined efficacy of aerosolized miR-138-5p and miR-200c miRNA mimics in lung cancer prevention. Combination of the two miRNAs inhibited Benzo(a)pyrene (B((a))P)-induced lung adenomas and N-nitroso-tris-chloroethylurea (NTCU)-induced lung squamous cell carcinomas with no detectable side effects. Using single-cell RNA sequencing (scRNA-seq) and imaging mass cytometry (IMC), we found that both miRNAs inhibited programmed cell death ligand 1 (PD-L1) expression. Our flow cytometry results showed that aerosolized delivery of combined miRNAs increased CD4+ and CD8+ T cells and reduced the expression of programmed cell death protein 1 (PD-1) and T-regulatory cells. Our results demonstrated that the delivery of aerosolized microRNAs targeting PD-L1 can be highly effective in preventing lung cancer development and progression in mice.
Insights
Inhaled microRNAs (miRNAs) show promise for lung cancer prevention by inhibiting tumor growth and enhancing anti-tumor immunity. This study demonstrates a novel aerosolized miRNA combination effectively prevents lung cancer in mice without side effects.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lung cancer remains a leading cause of cancer mortality worldwide.
- Chemoprevention strategies are crucial for reducing lung cancer incidence and progression.
- Novel drug delivery systems, like inhalation, offer targeted therapeutic approaches for lung diseases.
Purpose of the Study:
- To investigate the combined efficacy of aerosolized miR-138-5p and miR-200c miRNA mimics for lung cancer prevention.
- To evaluate the impact of these miRNA mimics on tumor development and immune responses in a mouse model.
- To explore the underlying molecular mechanisms, including programmed cell death ligand 1 (PD-L1) expression and T-cell modulation.
Main Methods:
- Utilized a mouse model to assess lung cancer prevention using aerosolized miRNA mimics.
- Administered specific miRNA mimics (miR-138-5p and miR-200c) via inhalation.
- Employed single-cell RNA sequencing (scRNA-seq) and imaging mass cytometry (IMC) to analyze molecular changes.
- Conducted flow cytometry to assess T-cell populations and immune checkpoint protein expression (PD-1).
Main Results:
- The combination of aerosolized miR-138-5p and miR-200c effectively inhibited lung adenomas and squamous cell carcinomas induced by chemical carcinogens (B((a))P and NTCU).
- No detectable side effects were observed with the combined miRNA treatment.
- Both miRNAs were found to inhibit programmed cell death ligand 1 (PD-L1) expression.
- Aerosolized miRNA delivery increased CD4+ and CD8+ T cells while reducing regulatory T-cells and programmed cell death protein 1 (PD-1) expression.
Conclusions:
- Aerosolized delivery of combined miR-138-5p and miR-200c miRNA mimics represents a novel and effective strategy for lung cancer chemoprevention.
- Targeting PD-L1 with inhaled miRNAs can enhance anti-tumor immunity and prevent lung cancer development and progression.
- This approach holds significant potential for reducing lung cancer morbidity and mortality.
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