Tumor inflammation promotes angiogenesis, immunosuppression, and tumor growth. Tumor associated myeloid cells, which include incompletely differentiated myeloid derived suppressor cells, macrophages and granulocytes, establish an immunosuppressive microenvironment in tumors through the expression of Arginase-1, which depletes the tumor microenvironment of arginine, thereby promoting T cell death and NK cell inhibition. Suppression of Arginase-1 expression and function could alter the course of cancer therapy by stimulating anti-tumor immunity to work in concert with anti-tumor vaccine or chemotherapeutic agents targeting tumor cell proliferation and survival. We found that myeloid cells express Arginase-1 in response to IL-6 stimulation in a Jak2/Stat3 and PI3Kinase gamma/mTORc1 dependent manner by promoting the activation of the transcriptional enhancer C/EBPbeta. Pharmacological or genetic blockade of Jak2, Stat3, PI3Kgamma, mTOR or C/EBPbeta suppressed expression of Arginase-1. Suppression of PI3Kgamma or Arginase-1 expression blocked myeloid cell induced death of T cells in vitro. PI3Kgamma inhibition blocked Arginase-1 expression in vivo, thereby increasing the number of CD8+ T cells in tumors, stimulating T cell-mediated cytotoxicity of tumor cells in vivo and suppressing growth and metastasis of implanted and spontaneous tumors. These studies reveal that suppression of Arginase-1 expression with PI3Kgamma or Jak2/Stat3 inhibitors can serve as an effective therapeutic strategy in oncology.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 411. doi:1538-7445.AM2012-411