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

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.