Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Cell Rep. 2012 Dec 27;2(6):1697-709. doi: 10.1016/j.celrep.2012.10.025. Epub 2012 Nov 29.
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.
为了提高针对人类癌症的基于细胞的免疫疗法，有必要加深对肿瘤免疫的理解。在这里，我们研究了两种免疫系统表达的 microRNA（miRNA），miR-155 和 miR-146a，在调节抗肿瘤免疫反应中的作用。我们的结果表明，miR-155 通过 T 细胞促进和 miR-146a 抑制干扰素 γ（IFNγ）反应，并减少体内实体瘤的生长。使用双重敲除（DKO）小鼠品系，该品系缺乏 miR-155 和 miR-146a，我们还确定了这两种 miRNA 之间的上位关系。DKO 小鼠的 T 细胞反应和肿瘤生长表型与 miR-155(-/-) 小鼠缺陷相似。对 T 细胞区室的进一步分析表明，miR-155 通过涉及抑制 Ship1 的机制来调节 IFNγ 的表达。我们的工作揭示了 miRNA 在 CD4(+)和 CD8(+)T 细胞介导的抗肿瘤免疫的相互调节中的关键作用，并证明了 miR-155 在促进免疫反应中的主导地位。
