@article{723b315a6f904dc79bbf3565782eee7c,
title = "Glioblastoma Myeloid-Derived Suppressor Cell Subsets Express Differential Macrophage Migration Inhibitory Factor Receptor Profiles That Can Be Targeted to Reduce Immune Suppression",
abstract = "The application of tumor immunotherapy to glioblastoma (GBM) is limited by an unprecedented degree of immune suppression due to factors that include high numbers of immune suppressive myeloid cells, the blood brain barrier, and T cell sequestration to the bone marrow. We previously identified an increase in immune suppressive myeloid-derived suppressor cells (MDSCs) in GBM patients, which correlated with poor prognosis and was dependent on macrophage migration inhibitory factor (MIF). Here we examine the MIF signaling axis in detail in murine MDSC models, GBM-educated MDSCs and human GBM. We found that the monocytic subset of MDSCs (M-MDSCs) expressed high levels of the MIF cognate receptor CD74 and was localized in the tumor microenvironment. In contrast, granulocytic MDSCs (G-MDSCs) expressed high levels of the MIF non-cognate receptor CXCR2 and showed minimal accumulation in the tumor microenvironment. Furthermore, targeting M-MDSCs with Ibudilast, a brain penetrant MIF-CD74 interaction inhibitor, reduced MDSC function and enhanced CD8 T cell activity in the tumor microenvironment. These findings demonstrate the MDSC subsets differentially express MIF receptors and may be leveraged for specific MDSC targeting.",
keywords = "MDSC, MIF–macrophage migration inhibitory factor, glioma, immunesuppresion, immunetherapy",
author = "Alban, {Tyler J.} and Defne Bayik and Balint Otvos and Anja Rabljenovic and Lin Leng and Leu Jia-Shiun and Gustavo Roversi and Adam Lauko and Momin, {Arbaz A.} and Mohammadi, {Alireza M.} and Peereboom, {David M.} and Ahluwalia, {Manmeet S.} and Kazuko Matsuda and Kyuson Yun and Richard Bucala and Vogelbaum, {Michael A.} and Lathia, {Justin D.}",
note = "Funding Information: We thank the members of the Lathia laboratory for insightful discussion and constructive comments on the manuscript. We thank Joseph Gerow and Eric Schultz for flow cytometry assistance. We thank Amanda Mendelsohn and the Center for Medical Art and Photography at the Cleveland Clinic for providing illustrations and Dr. Erin Mulkearns-Hubert for editorial assistance. We also thank Medicnova for supplying Ibudilast for our studies and their collaborative efforts. Funding. This work was funded by an NIH grant (R01 NS109742 to JL and MAVF31, F31 NS101771 to TA, F32 CA243314 to DB) the Sontag Foundation (JL), Blast GBM (JL and MV), the Cleveland Clinic VeloSano Bike Race (JL and MV), B*CURED (JL and MV), the Case Comprehensive Cancer Center (JL and MV), and the Cleveland Clinic Brain Tumor Research and Therapeutic Development Research Center of Excellence (MA and JL). Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Alban, Bayik, Otvos, Rabljenovic, Leng, Jia-Shiun, Roversi, Lauko, Momin, Mohammadi, Peereboom, Ahluwalia, Matsuda, Yun, Bucala, Vogelbaum and Lathia. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = jun,
day = "18",
doi = "10.3389/fimmu.2020.01191",
language = "English (US)",
volume = "11",
journal = "Frontiers in immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
}