Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity

Cell Rep. 2012 Dec 27;2(6):1697-709. doi: 10.1016/j.celrep.2012.10.025. Epub 2012 Nov 29.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Epistasis, Genetic / genetics
  • Epistasis, Genetic / immunology*
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / immunology*
  • Humans
  • Immunity, Cellular*
  • Inositol Polyphosphate 5-Phosphatases
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Mice
  • Mice, Knockout
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics
  • MicroRNAs / immunology*
  • 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

Substances

  • MicroRNAs
  • Mirn146 microRNA, mouse
  • Mirn155 microRNA, mouse
  • Interferon-gamma
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • INPP5D protein, human
  • Inpp5d protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases