Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
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.
View: Text | PDF
Research Article Angiogenesis Immunology

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

  • Text
  • PDF
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

×

Figure 11

Increased cytotoxic program and phenotype in CD8+ TILs is the result of miR-21 deletion in macrophages.

Options: View larger image (or click on image) Download as PowerPoint
Increased cytotoxic program and phenotype in CD8+ TILs is the result of ...
(A) Overlaid t-SNE plots colored by sample of CD45+ cells isolated from s.c. LLC tumors of miR-21fl/fl and LysMCre;miR-21fl/fl mice. (B) Recolored t-SNE plot based on matching results for the combined dataset distinct groups of cells separated and manifested. See feature plots of select marker gene overlays in Supplemental Figure 2A. (C) Dot plot analysis of differentially expressed genes in CD8+T cells of s.c. LLC tumor immune infiltrate of LysMCre;miR-21fl/fl or LysMCre;miR-21fl/fl mice. (D) IPA analysis of set of genes differentially regulated in CD8+ T cells from s.c. LLC tumors of LysMCre;miR-21fl/fl versus miR-21fl/fl mice. Dot size represents the fraction of cells expressing the gene, and red color represents a greater than 1.5-fold gene expression among expressing cells. (E) IPA network analysis using Regulator Effects algorithm of gene set differentially regulated in CD8+ T cells from LLC tumors of LysMCre;miR-21fl/fl versus miR-21fl/fl mice.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts