IMMU-17. LEVERAGING CORE EPIGENETIC PROGRAMMING OF IMMUNOSUPPRESSIVE MYELOID CELLS FOR THERAPEUTIC TARGETING OF GLIOBLASTOMA

Abstract Accumulation of various immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), facilitates progression and treatment resistance glioblastoma (GBM). We previous demonstrated that monocytic MDSCs (mMDSCs) but not granulocytic (gMDSCs) infiltrate tumors in mouse models patients, nonspecific targeting mMDSCs with chemotherapies provided therapeutic benefit preclinical GBM. To investigate the differential role trafficking versus gMDSCs GBM, we adoptively transferred these into tumor-bearing mice. Mice received succumbed to disease at an earlier point compared control mice or gMDSCs. delineate cellular basis this distinct behavior MDSC subsets, performed assay for transposase-accessible chromatin using sequencing (ATAC-seq) observed cell adhesion-related genes were significantly enriched open regions as opposed Aligned epigenetic profile, from blood had higher surface integrin β1 expression both GBM patients. evaluate functional integrins, pre-treated anti-integrin prior adoptive transfer. Blockade interfered pro-tumorigenic mMDSCs, survival span receiving was similar vehicle controls. Further analysis ATAC-Seq data revealed dipeptidyl peptidase-4 (Dpp4), interacting partner β1, more accessible gMDSC. Consistently, bone marrow-derived tumor-infiltrating patients expressed high levels Dpp4. Pharmacological inhibition Dpp4 reduced chemotaxis vitro extended duration tumors. The findings study have broad implications across cancer types modulate by leveraging novel insights their adhesion mechanisms.