ME-13 * LOSS OF SOCS3 IN MYELOID CELLS DELAYS TUMOR GROWTH AND PROLONGS SURVIVAL IN A SYNGENEIC MODEL OF GLIOBLASTOMA

Abstract

Glioblastoma (GBM), a particularly devastating type of brain tumor, remains a challenging and difficult disease to treat. Despite aggressive therapies, patients diagnosed with GBM have a median survival of 12-16 months. On a cellular level, GBM tumors are extremely heterogeneous, consisting of resident tumor cells, tumor initiating cells, infiltrating immune cells, endothelial cells, and other tumor associated stromal cells, which makes developing targeted therapies a challenge. In GBM, microglia (MG) and macrophages (MP) are the largest population of tumor-infiltrating cells. GBM tumor cells recruit MG/MP via the secretion of chemo-attractants; however, upon arrival at the tumor, the MG/MP adopt an anti-inflammatory phenotype, and in turn accidentally aide in tumor promotion through the secretion of various cytokines. We have previously determined that macrophages with deletion of Suppressor of Cytokine Signaling 3 (SOCS3), the negative regulator of Signal Transducer and Activator of Transcription 3 (STAT3), have an enhanced M1 (pro-inflammatory) response. Herein, we sought to determine the role of SOCS3 in MG/MP functionality in GBM. In this report, we utilized a conditional model in which SOCS3 deletion is restricted to the myeloid cell population. We found that deletion of SOCS3 in the myeloid cell population delays intracranial tumor growth and increases survival of mice bearing orthotopic glioma tumors. Intracranial tumors from mice with SOCS3 deficient myeloid cells have an increase in the number of infiltrating immune cells, including monocytes, neutrophils and macrophages. Lastly, SOCS3 deficient bone marrow derived macrophages display enhanced and prolonged expression of pro-inflammatory M1 cytokines (TNF-α, IL-6) when exposed to tumor cell conditioned medium in vitro. Therefore, loss of SOCS3 in MG/MP in the tumor promotes an inflammatory, immune response early and thus delays tumor growth. These preliminary findings highlight an important role of the STAT3/SOCS3 signaling axis in MG/MP in GBM tumors.