Epistasis between MicroRNAs 155 and 146a during T Cell-Mediated Antitumor Immunity
Thomas B. Huffaker,
Ruozhen Hu,
Marah C. Runtsch,
Erin Bake,
Xinjian Chen,
Jimmy Zhao,
June L. Round,
David Baltimore,
Ryan M. O'Connell
Affiliations
Thomas B. Huffaker
Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Jones Medical Research Building, Salt Lake City, UT 84112, USA
Ruozhen Hu
Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Jones Medical Research Building, Salt Lake City, UT 84112, USA
Marah C. Runtsch
Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Jones Medical Research Building, Salt Lake City, UT 84112, USA
Erin Bake
Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Jones Medical Research Building, Salt Lake City, UT 84112, USA
Xinjian Chen
Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Jones Medical Research Building, Salt Lake City, UT 84112, USA
Jimmy Zhao
Division of Biology, California Institute of Technology, 330 Braun, 1200 E. California Boulevard, Pasadena, CA 91125, USA
June L. Round
Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Jones Medical Research Building, Salt Lake City, UT 84112, USA
David Baltimore
Division of Biology, California Institute of Technology, 330 Braun, 1200 E. California Boulevard, Pasadena, CA 91125, USA
Ryan M. O'Connell
Division of Microbiology and Immunology, Department of Pathology, University of Utah, 15 N. Medical Drive East, Jones Medical Research Building, Salt Lake City, UT 84112, USA
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.
