MiR-17-92 expression in differentiated T cells - implications for cancer immunotherapy

Kotaro Sasaki, Gary Kohanbash, Aki Hoji, Ryo Ueda, Heather A. McDonald, Todd A. Reinhart, Jeremy Martinson, Michael T. Lotze, Francesco M. Marincola, Ena Wang, Mitsugu Fujita, Hideho Okada

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Abstract

Background: Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated.Methods: We performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells.Results: Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-γ production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD).Conclusion: The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy.

Original languageEnglish
Article number17
JournalJournal of translational medicine
Volume8
DOIs
Publication statusPublished - 18 Feb 2010

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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Sasaki, K., Kohanbash, G., Hoji, A., Ueda, R., McDonald, H. A., Reinhart, T. A., Martinson, J., Lotze, M. T., Marincola, F. M., Wang, E., Fujita, M., & Okada, H. (2010). MiR-17-92 expression in differentiated T cells - implications for cancer immunotherapy. Journal of translational medicine, 8, [17]. https://doi.org/10.1186/1479-5876-8-17