Epistasis between MicroRNAs 155 and 146a during T Cell-Mediated Antitumor Immunity

• Published in: Cell reports (Cambridge) 2012-12, Vol.2 (6), p.1697-1709
• Main Authors: Huffaker, Thomas B., Hu, Ruozhen, Runtsch, Marah C., Bake, Erin, Chen, Xinjian, Zhao, Jimmy, Round, June L., Baltimore, David, O'Connell, Ryan M.
• Format: Article
• Language: English
• Subjects: Animals; Antitumor activity; Cancer vaccines; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cell Line, Tumor; Epistasis; Epistasis, Genetic - genetics; Epistasis, Genetic - immunology; gamma -Interferon; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - immunology; Humans; Immunity (cell-mediated); Immunity, Cellular; Immunotherapy; Inositol Polyphosphate 5-Phosphatases; Interferon-gamma - biosynthesis; Interferon-gamma - genetics; Interferon-gamma - immunology; Lymphocytes T; Mice; Mice, Knockout; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - immunology; miRNA; Neoplasms, Experimental - genetics; Neoplasms, Experimental - immunology; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - immunology; Phosphoric Monoester Hydrolases - metabolism; Solid tumors; Tumors
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.10.025

An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs), miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ) responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO) mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155−/− mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4+ and CD8+ T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses. [Display omitted] ► miR-155 promotes and miR-146a inhibits both CD4+ and CD8+ T cell antitumor responses ► DKO mice reveal epistasis between miR-155 and miR-146a during tumor immunity ► miR-155 regulation of IFNγ involves repression of its target Ship1 in T cells There is growing interest in identifying factors that regulate antitumor immune responses. O'Connell and colleagues find that miR-155 and miR-146a play pivotal yet contrasting roles during CD4+ and CD8+ T cell-mediated tumor immunity. Through the use of mice deficient in both miRNAs, they also determine that miR-155 is dominant to miR-146a during this response. These findings indicate that therapeutic manipulation of these specific miRNAs in T cells could reprogram the tumor microenvironment and restrict tumor growth.