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.
Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.
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