Pulmonary Aerosol Delivery of Let‐7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment
Abstract 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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-09-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202100629 |
| _version_ | 1819239968432717824 |
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| author | Qi Zhang Jing Pan Donghai Xiong Yian Wang Mark Steven Miller Shizuko Sei Robert H. Shoemaker Alberto Izzotti Ming You |
| author_facet | Qi Zhang Jing Pan Donghai Xiong Yian Wang Mark Steven Miller Shizuko Sei Robert H. Shoemaker Alberto Izzotti Ming You |
| author_sort | Qi Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-23T14:00:33Z |
| format | Article |
| id | doaj.art-15a5fafd15a24128b26bf1acb559b37c |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-23T14:00:33Z |
| publishDate | 2021-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-15a5fafd15a24128b26bf1acb559b37c2022-12-21T17:44:19ZengWileyAdvanced Science2198-38442021-09-01817n/an/a10.1002/advs.202100629Pulmonary Aerosol Delivery of Let‐7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune MicroenvironmentQi Zhang0Jing Pan1Donghai Xiong2Yian Wang3Mark Steven Miller4Shizuko Sei5Robert H. Shoemaker6Alberto Izzotti7Ming You8Center for Disease Prevention Research Medical College of Wisconsin Milwaukee WI 53226 USACenter for Disease Prevention Research Medical College of Wisconsin Milwaukee WI 53226 USACenter for Disease Prevention Research Medical College of Wisconsin Milwaukee WI 53226 USACenter for Disease Prevention Research Medical College of Wisconsin Milwaukee WI 53226 USAChemopreventive Agent Development Research Group Division of Cancer Prevention National Cancer Institute Bethesda MD 20892 USAChemopreventive Agent Development Research Group Division of Cancer Prevention National Cancer Institute Bethesda MD 20892 USAChemopreventive Agent Development Research Group Division of Cancer Prevention National Cancer Institute Bethesda MD 20892 USADepartment of Experimental Medicine University of Genoa Genoa 16132 ItalyCenter for Disease Prevention Research Medical College of Wisconsin Milwaukee WI 53226 USAAbstract 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.https://doi.org/10.1002/advs.202100629immunitylet‐7blung cancermiRNApulmonary aerosol deliverysingle‐cell RNA sequencing |
| spellingShingle | Qi Zhang Jing Pan Donghai Xiong Yian Wang Mark Steven Miller Shizuko Sei Robert H. Shoemaker Alberto Izzotti Ming You Pulmonary Aerosol Delivery of Let‐7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment Advanced Science immunity let‐7b lung cancer miRNA pulmonary aerosol delivery single‐cell RNA sequencing |
| title | Pulmonary Aerosol Delivery of Let‐7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment |
| title_full | Pulmonary Aerosol Delivery of Let‐7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment |
| title_fullStr | Pulmonary Aerosol Delivery of Let‐7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment |
| title_full_unstemmed | Pulmonary Aerosol Delivery of Let‐7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment |
| title_short | Pulmonary Aerosol Delivery of Let‐7b microRNA Confers a Striking Inhibitory Effect on Lung Carcinogenesis through Targeting the Tumor Immune Microenvironment |
| title_sort | pulmonary aerosol delivery of let 7b microrna confers a striking inhibitory effect on lung carcinogenesis through targeting the tumor immune microenvironment |
| topic | immunity let‐7b lung cancer miRNA pulmonary aerosol delivery single‐cell RNA sequencing |
| url | https://doi.org/10.1002/advs.202100629 |
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