TMIC-29. MYELOID DERIVED SUPPRESSOR CELLS’ TRAFFICKING INTO GBM IS REGULATED BY CXCR2 SIGNALING

Abstract

Survival of glioma patients treated with the current standard of care remains dismal. Immunotherapeutic approaches harnessing the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. It is imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. MDSC depletion strongly enhanced the efficacy of herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Overall, our data indicates that strategies that inhibit MDSC recruitment to the GBM TME hold great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM. Experiments to determine the mechanism of MDSC trafficking to the TME point towards the receptor CXCR2. Microarray analysis of glioma cell lines and neurospheres showed elevated levels of CXCL1 and CXCL2 mRNA. CXCR2 inhibitor suppressed the migration of MDSCs towards GBM cells in a transwell migration assay. Conditioned media from GBM neurospheres also enhanced the permeability of an in vitro blood brain barrier model as indicated by the increased migration of size exclusion dyes. Blocking CXCR2 on endothelial cells and/or pericytes abrogated this increase in BBB permeability. Thus our data suggests that the CXCR2 receptor can regulate MDSC migration into the TME by directly impacting MDSC migration or by altering the BBB permeability. Future experiments are aimed at using the Vav-Cre mediated conditional deletion of CXCR2 on myeloid cells and pharmacological inhibition of CXCR2 to investigate its role in glioma progression in vivo.