TMIC-15. MYELOID DERIVED SUPPRESSOR CELLS’ TRAFFICKING INTO GBM IS REGULATED BY CXCR2 SIGNALING Neha Kamran, Stefanie Stallard, Nicholas Raja, Mariela-Moreno Ayala, Alexandra Calinescue, Felipe Nunez, Anuska Andjelkovic, Pedro Lowenstein, and Maria Castro; University of Michigan, Ann Arbor, MI, USA MDSCs represent a population of immature myeloid cells at various stages of differentiation that have the potential to inhibit anti-tumor T cell immunity. We demonstrate the accumulation of MDSCs in the tumor microenvironment (TME) of glioma (GBM) bearing mice. In vivo, when combined with Ad-TK + Ad-FLT3L immune stimulatory-gene therapy, MDSC depletion significantly
enhanced the frequency of tumor-specific T cells within the TME and increased IFN-g production by splenic T cells. A trend for increased IFN-g+ CD8 T cells within the glioma TME was also observed. The enhanced CD8 T cell activity was accompanied by a significant increase in survival of GBM bearing animals. Our data therefore indicates that inhibiting the accumulation of MDSCs within the GBM TME promotes the generation of robust anti-tumor immunity. Preliminary experiments to determine the mechanism of MDSC trafficking to the TME point towards the receptor CXCR2 and its ligands CXCL1 and CXCL2. Protein analysis of glioma cell lines showed abundant secretion of CXCL1 and CXCL2 chemokines. Additionally brain endothelial cells and glial cells when stimulated with GBM cell lysates released increased levels of CXCL1. CXCL1 levels were also observed to be elevated in the serum of GBM bearing animals. SB225002, a CXCR2 inhibitor suppressed the migration of MDSCs towards GBM cells in an in vitro transwell migration assay. Using an in vitro model we also show that conditioned media from GBM cell lines and neurospheres increases the permeability of the blood brain barrier (BBB) by remodeling of the tight junction complexes in a CXCR2 dependent manner that further aids in the infiltration of MDSCs through the BBB. Further experiments are underway to determine the effect of CXCR2 blocking in BBB permeability, MDSC trafficking and glioma progression in vivo.
Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.
