MiR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma

Jun Wei, Fei Wang, Ling Yuan Kong, Shuo Xu, Tiffany Doucette, Sherise D. Ferguson, Yuhui Yang, Kayla McEnery, Krishan Jethwa, Olsi Gjyshi, Wei Qiao, Nicholas B. Levine, Frederick F. Lang, Ganesh Rao, Gregory N. Fuller, George A. Calin, Amy B. Heimberger*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

167 Scopus citations

Abstract

miRNAs (miR) have been shown to modulate critical gene transcripts involved in tumorigenesis, but their role in tumor-mediated immunosuppression is largely unknown. On the basis of miRNA gene expression in gliomas using tissue microarrays, in situ hybridization, and molecular modeling, miR-124 was identified as a lead candidate for modulating STAT3 signaling, a key pathway mediating immunosuppression in the tumor microenvironment. miR-124 is absent in all grades and pathologic types of gliomas. Upon upregulating miR- 124 in glioma cancer stem cells (gCSC), the STAT3 pathway was inhibited, and miR-124 reversed gCSC-mediated immunosuppression of T-cell proliferation and induction of forkhead box P3 (Foxp3)+ regulatory T cells (Treg). Treatment of T cells from immunosuppressed glioblastoma patients with miR-124 induced marked effector response including upregulation of interleukin (IL)-2, IFN-γ, and TNF-α. Both systemic administration of miR-124 or adoptive miR-124-transfected T-cell transfers exerted potent anti-glioma therapeutic effects in clonotypic and genetically engineered murine models of glioblastoma and enhanced effector responses in the local tumor microenvironment. These therapeutic effects were ablated in both CD4+- and CD8 +-depleted mice and nude mouse systems, indicating that the therapeutic effect of miR-124 depends on the presence of a T-cell-mediated antitumor immune response. Our findings highlight the potential application of miR-124 as a novel immunotherapeutic agent for neoplasms and serve as a model for identifying miRNAs that can be exploited as immunotherapeutics.

Original languageEnglish (US)
Pages (from-to)3913-3926
Number of pages14
JournalCancer Research
Volume73
Issue number13
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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