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

J Wei, F Wang, LY Kong, S Xu, T Doucette… - Cancer research, 2013 - AACR
J Wei, F Wang, LY Kong, S Xu, T Doucette, SD Ferguson, Y Yang, K McEnery, K Jethwa…
Cancer research, 2013AACR
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 …
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. Cancer Res; 73(13); 3913–26. ©2013 AACR.
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