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Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response
Mahnaz Sahraei, … , Carlos Fernández-Hernando, Yajaira Suárez
Mahnaz Sahraei, … , Carlos Fernández-Hernando, Yajaira Suárez
Published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5518-5536. https://doi.org/10.1172/JCI127125.
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Research Article Angiogenesis Immunology

Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response

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Abstract

microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.

Authors

Mahnaz Sahraei, Balkrishna Chaube, Yuting Liu, Jonathan Sun, Alanna Kaplan, Nathan L. Price, Wen Ding, Stanley Oyaghire, Rolando García-Milian, Sameet Mehta, Yana K. Reshetnyak, Raman Bahal, Paolo Fiorina, Peter M. Glazer, David L. Rimm, Carlos Fernández-Hernando, Yajaira Suárez

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Figure 4

High expression of miR-21 in CD68+ cells of the TME of NSCLC regulates disease outcome.

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High expression of miR-21 in CD68+ cells of the TME of NSCLC regulates d...
(A–C) Kaplan-Meier 5-year OS survival curves of patients with NSCLC in a combined analysis of 3 Yale cohorts; patients were stratified by the median of normalized miR-21–positive cell counts in (A) TIs, (B) TME, and (C) total cells. (D) Quantitative immunofluorescence of miR-21 in TI and TME cell compartments. (E) Quantitative immunofluorescence intensity of miR-21 in CD68+ cells in TI and TME cell compartments. (F) Analysis of the percentage of miR-21+ Cd68+ of total miR-21+ cells in the 3 Yale cohorts independently and combined. (G) Representative cytokeratin immunostaining, miR-21 FISH, and CD68 immunostaining of a random spot of YTMA250. Dashed lines delimit TI (cytokeratin-enriched areas) from TME. Arrowheads no. 1 and no. 2 indicate cytoketatin+ cells in TI with high or low miR-21 intensity, respectively. Arrows no. 3 and no. 4 indicate CD68+ cells in TME with high or low miR-21 intensity, respectively. Arrows no. 5 and no. 6 indicate CD68+ cells in TI with high or low miR-21 intensity, respectively. Scale bar: 100 μm. (H–J) Kaplan-Meier OS survival curves of patients with NSCLC in a combined analysis of 3 Yale cohorts; patients were stratified by the top tertile of normalized double-positive cell counts (miR-21+ CD68+) in (H) TI, (I) TME, and (J) total cells. (A–C and H–J) Kaplan–Meier survival curves compared by log-rank test. *P < 0.05.
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