title: miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma.
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.
authors: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230, USA.
authors: Jun
authors: J
authors: Wei
authors: Fei
authors: F
authors: Wang
authors: Ling-Yuan
authors: LY
authors: Kong
authors: Shuo
authors: S
authors: Xu
authors: Tiffany
authors: T
authors: Doucette
authors: Sherise D
authors: SD
authors: Ferguson
authors: Yuhui
authors: Y
authors: Yang
authors: Kayla
authors: K
authors: McEnery
authors: Krishan
authors: K
authors: Jethwa
authors: Olsi
authors: O
authors: Gjyshi
authors: Wei
authors: W
authors: Qiao
authors: Nicholas B
authors: NB
authors: Levine
authors: Frederick F
authors: FF
authors: Lang
authors: Ganesh
authors: G
authors: Rao
authors: Gregory N
authors: GN
authors: Fuller
authors: George A
authors: GA
authors: Calin
authors: Amy B
authors: AB
authors: Heimberger
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D007108:Immune Tolerance; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D016207:Cytokines; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
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