Aerosolized miR-138-5p and miR-200c targets PD-L1 for lung cancer chemoprevention

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](a))P)-induced lung adenomas and N-nitroso-tris-chloroethylurea (NTCU)-induced lung squamous 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 results demonstrated that the delivery of aerosolized microRNAs targeting PD-L1 can be highly effective in preventing lung cancer development and progression in mice.

能够阻断肺部病变进展为恶性肿瘤的化学预防策略的研发，将降低这一致命疾病所导致的死亡率与发病率。经吸入递送微小核糖核酸（microRNA, miRNA）是一种全新的肺癌预防方法。本研究探究了雾化型miR-138-5p与miR-200c miRNA模拟物联合应用于肺癌预防的协同功效。两种miRNA联合使用可抑制苯并(a)芘（Benzo(a)pyrene）诱导的肺腺瘤，以及N-亚硝基三氯乙基脲（N-nitroso-tris-chloroethylurea, NTCU）诱导的肺鳞状细胞癌，且未检测到明显副作用。本研究借助单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）与成像质谱流式细胞术（imaging mass cytometry, IMC），发现两种miRNA均可抑制程序性死亡受体配体1（programmed cell death ligand 1, PD-L1）的表达。本研究结果证实，递送靶向PD-L1的雾化型miRNA，可在小鼠模型中高效阻断肺癌的发生与进展。