Abstract B62: miR-124 systemically enhances antitumor clearance by inhibiting STAT3 signaling and reversing glioma-associated immune suppression.

Abstract

Abstract MicroRNAs (miRs) have been shown to modulate critical gene transcripts involved in tumorigenesis, but their role in tumor-mediated immune suppression is largely unknown. In this study, we evaluated miRNAs that are preferentially down-regulated in glioblastoma and that interact with immune suppressive pathways as potential new therapeutics. On the basis of miRNA-gene expression libraries of glioblastoma, tissue microarrays, and molecular modeling, we selected miR-124 as the lead candidate for modulating signal transducer and activator of transcription 3 (STAT3) signaling, a key pathway mediating immune suppression of the tumor microenvironment. Upon up regulating miR-124 in glioma cancer stem cells (gCSCs), the STAT3 pathway was inhibited and the miR-124 reversed gCSC-mediated immune suppression of T cell proliferation and Th1 polarization and decreased gCSC-induced Foxp3+ regulatory T cells (Tregs). Treatment of immune-suppressed glioblastoma patient T cells with miR-124 induced marked effector response including up regulation of 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 nude murine systems. Our findings highlight the potential application of miR-124 as a novel immunotherapeutic agent for neoplasm treatment by exploiting the immune system to mediate direct tumor cytotoxicity. Citation Format: Jun Wei, Ling-Yuan Kong, Fei Wang, Shuo Xu, Tiffany Doucette, Sherise D. Ferguson, Yuhui Yang, Kayla McEnery, Krishan Jethwa, Olsi Gjyshi, Wei Qiao, Frederick Lang, Ganesh Rao, Greg N. Fuller, George A. Calin, Amy B. Heimberger. miR-124 systemically enhances antitumor clearance by inhibiting STAT3 signaling and reversing glioma-associated immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B62.