Center for Cancer Prevention, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, United States.
Center for Immunotherapy Research, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, United States.
Front Immunol. 2023 Jul 13;14:1166951. doi: 10.3389/fimmu.2023.1166951. eCollection 2023.
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.
开发具有预防肺病变进展为恶性癌症能力的化学预防策略，将降低这种致命疾病导致的死亡率和发病率。通过吸入将 microRNA（miRNA）递送至肺部是一种用于预防肺癌的新方法。在这项研究中，我们研究了雾化 miR-138-5p 和 miR-200c miRNA 模拟物联合在肺癌预防中的疗效。两种 miRNA 的联合抑制了苯并（a）芘（B（a）P）诱导的肺腺癌和 N-亚硝基三氯乙基亚硝脲（NTCU）诱导的肺鳞癌，没有发现任何副作用。使用单细胞 RNA 测序（scRNA-seq）和成像质谱流式细胞术（IMC），我们发现两种 miRNA 均抑制程序性细胞死亡配体 1（PD-L1）的表达。我们的流式细胞术结果表明，联合 miRNA 的雾化递送增加了 CD4+和 CD8+T 细胞，并降低了程序性死亡蛋白 1（PD-1）和 T 调节细胞的表达。我们的结果表明，针对 PD-L1 的雾化 microRNA 的递送可在预防小鼠肺癌发生和进展方面非常有效。
