TMIC-17LOSS OF SOCS3 IN MYELOID CELLS PROMOTES A DECREASED M2 MACROPHAGE PHENOTYPE AND AN INCREASED CYTOTOXIC T-CELL RESPONSE IN A SYNGENEIC MODEL OF GLIOMA

Abstract

Glioblastoma (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 and macrophages are the largest population of tumor-infiltrating cells, herein referred to as tumor associated macrophages (TAMs).GBMtumor cells recruit TAMs via the secretion of chemo-attractants; however, upon arrival at the tumor, TAMsadopt an immunosuppressive phenotype, and 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 TAM 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 SOCS3 deficient bone marrow-derived macrophages display enhanced and prolonged expression of pro-inflammatory M1 cytokines when exposed to tumor cell conditioned medium in vitro. Moreover, we found that deletion of SOCS3 in the myeloid cell population delays intracranial tumor growth and increases survival of mice bearing orthotopic glioma tumors in vivo. Although the intracranial tumors from mice with SOCS3deficient myeloid cells appear histologically similar to control mice, we observed that loss of SOCS3 in myeloid cells results in decreasedM2polarized macrophage infiltration in the tumors. Furthermore, loss of SOCS3 in myeloid cells results in increased CD8+ T-cell and decreased regulatory T-cell infiltration in the tumors. Therefore, loss of SOCS3 in TAMs 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 TAMs in GBM tumors.