Pulmonary Aerosol Delivery of Let-7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment,Advanced Science

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Pulmonary Aerosol Delivery of Let-7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment
Advanced Science ( IF 14.3 ) Pub Date : 2021-07-08 , DOI: 10.1002/advs.202100629
Qi Zhang _{1,

2} , Jing Pan _{1,

2} , Donghai Xiong _{1,

2} , Yian Wang _{1,

2} , Mark Steven Miller ₃ , Shizuko Sei ₃ , Robert H Shoemaker ₃ , Alberto Izzotti _{4,

5} , Ming You _{1,

2}

Affiliation

MicroRNAs are potential candidates for lung cancer prevention and therapy. A major limitation is the lack of an efficient delivery system to directly deliver miRNA to cancer cells while limiting systemic exposure. The delivery of miRNA via inhalation is a potential strategy for lung cancer prevention in high-risk individuals. In this study, the authors investigate the efficacy of aerosolized let-7b miRNA treatment in lung cancer prevention. Let-7b shows significant inhibition of B[a]P-induced lung adenoma with no detectable side effects. Single-cell RNA sequencing of tumor-infiltrating T cells from primary tumors reveals that Let-7b post-transcriptionally suppresses PD-L1 and PD-1 expression in the tumor microenvironment, suggesting that let-7b miRNAs may promote antitumor immunity in vivo. Let-7b treatment decreases the expression of PD-1 in CD8+ T cells and reduces PD-L1 expression in lung tumor cells. The results suggest that this aerosolized let-7b mimic is a promising approach for lung cancer prevention, and that the in vivo tumor inhibitory effects of let-7b are mediated, at least in part, by immune-promoting effects via downregulating PD-L1 in tumors and/or PD-1 on CD8+ T cells. These changes potentiate antitumor CD8+ T cell immune responses, and ultimately lead to tumor inhibition.

中文翻译：

Let-7b microRNA 的肺气溶胶递送通过靶向肿瘤免疫微环境对肺癌发生具有显着的抑制作用

MicroRNA 是肺癌预防和治疗的潜在候选者。主要限制是缺乏有效的递送系统来直接将 miRNA 递送至癌细胞，同时限制全身暴露。通过吸入递送 miRNA 是预防高危人群肺癌的潜在策略。在这项研究中，作者研究了雾化 let-7b miRNA 治疗在预防肺癌中的功效。 Let-7b 显示出对 B[a]P 诱导的肺腺瘤的显着抑制作用，且没有可检测到的副作用。来自原发性肿瘤的肿瘤浸润 T 细胞的单细胞 RNA 测序表明，Let-7b 在转录后抑制肿瘤微环境中的 PD-L1 和 PD-1 表达，表明 let-7b miRNA 可能促进体内抗肿瘤免疫。 Let-7b 治疗可降低 CD8+ T 细胞中 PD-1 的表达，并降低肺肿瘤细胞中 PD-L1 的表达。结果表明，这种雾化的let-7b模拟物是预防肺癌的一种有前景的方法，并且let-7b的体内肿瘤抑制作用至少部分是通过下调PD-L1的免疫促进作用来介导的。肿瘤和/或 CD8+ T 细胞上的 PD-1。这些变化增强了抗肿瘤 CD8+ T 细胞免疫反应，并最终抑制肿瘤。

更新日期：2021-09-09

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