TY - JOUR
T1 - Glioblastoma Myeloid-Derived Suppressor Cell Subsets Express Differential Macrophage Migration Inhibitory Factor Receptor Profiles That Can Be Targeted to Reduce Immune Suppression
AU - Alban, Tyler J.
AU - Bayik, Defne
AU - Otvos, Balint
AU - Rabljenovic, Anja
AU - Leng, Lin
AU - Jia-Shiun, Leu
AU - Roversi, Gustavo
AU - Lauko, Adam
AU - Momin, Arbaz A.
AU - Mohammadi, Alireza M.
AU - Peereboom, David M.
AU - Ahluwalia, Manmeet S.
AU - Matsuda, Kazuko
AU - Yun, Kyuson
AU - Bucala, Richard
AU - Vogelbaum, Michael A.
AU - Lathia, Justin D.
PY - 2020/6/18
Y1 - 2020/6/18
N2 - 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.
AB - 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.
KW - MDSC
KW - MIF–macrophage migration inhibitory factor
KW - glioma
KW - immunesuppresion
KW - immunetherapy
UR - http://www.scopus.com/inward/record.url?scp=85087443734&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087443734&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.01191
DO - 10.3389/fimmu.2020.01191
M3 - Article
C2 - 32625208
AN - SCOPUS:85087443734
VL - 11
JO - Frontiers in immunology
JF - Frontiers in immunology
SN - 1664-3224
M1 - 1191
ER -