Abstract 464: Hypoxia-induced miR-210 potentiates MDSC function through regulation of Arg1, Il-16 and Cxcl12, and promotes tumor growth

Abstract

Abstract Myeloid Derived Suppressor Cells (MDSCs) are an integral component of the hypoxic tumor microenvironment. We demonstrated that hypoxia selectively induced miR-210 via HIF-1α in splenic MDSCs from tumor-bearing mice. Overexpression of miR-210 enhanced MDSC-mediated T cell suppression under normoxia, while targeting of hypoxic miR-210 decreased MDSC function. Our data show that miR-210 modulated MDSCs function by increasing arginase activity and NO production, although it had no effect on ROS or cytokine (IL-6 and IL-10) production and PD-L1 expression. A comprehensive approach using microRNA target predictions tool, transcriptome analysis, and luciferase reporter assay strongly pointed to the regulation of Arg1, Cxcl12 and Il16 at both mRNA and protein levels by miR-210 in splenic MDSCs. In mediating the immunosuppressive effects of miR-210, targeting of Arg1, and blockade of IL-16 and CXCL12, in splenic MDSCs from tumor-bearing mice under normoxia dramatically decreased MDSC-mediated T cell proliferative response and IFN-gamma production. Interestingly, miR-210 overexpressing MDSCs enhanced in vivo their immune suppressive activity resulting in an increase in 4T1 tumor growth. Therefore, the potential therapeutic use of miR-210 inhibitor oligonucleotide alone, or along with HIF-1α inhibitors as adjuvant tool combined to immunotherapeutic approaches, may be beneficial for boosting the immune system in cancer patients. Citation Format: Muhammad Zaeem Noman, Salem Chouaib. Hypoxia-induced miR-210 potentiates MDSC function through regulation of Arg1, Il-16 and Cxcl12, and promotes tumor growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 464. doi:10.1158/1538-7445.AM2015-464