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.

Explicating the Pivotal Pathogenic, Diagnostic, and Therapeutic Biomarker Potentials of Myeloid-Derived Suppressor Cells in Glioblastoma

“…Macrophage migration inhibitory factor (MIF) is derived from GBM cells, precisely medicinally resistant cancer stem cells, and it is obligatory for MDSC survival and function [ 32 , 67 ]. Downregulation of MIF levels in GBM cells was incapable of modifying their proliferation [ 32 , 67 ].…”

“…Macrophage migration inhibitory factor (MIF) is derived from GBM cells, precisely medicinally resistant cancer stem cells, and it is obligatory for MDSC survival and function [ 32 , 67 ]. Downregulation of MIF levels in GBM cells was incapable of modifying their proliferation [ 32 , 67 ]. Nevertheless, an augmented host survival and an upsurge in the quantity of CD8 + T cells in the tumor microenvironment were observed when they were transplanted into an immune-proficient orthotopic model [ 32 , 67 , 68 ].…”

“…Downregulation of MIF levels in GBM cells was incapable of modifying their proliferation [ 32 , 67 ]. Nevertheless, an augmented host survival and an upsurge in the quantity of CD8 + T cells in the tumor microenvironment were observed when they were transplanted into an immune-proficient orthotopic model [ 32 , 67 , 68 ]. Also, MDSCs are capable of influencing macrophages resulting in inflammation as well as immunosuppressive effects in the tumor microenvironment [ 1 , 69 ].…”

“…MIF has demonstrated to be an appealing therapeutic target to reverse glioma-mediated MDSC buildup ( Figure 1(a) ) [ 32 , 36 ]. Kumar et al observed that administration of anti-MIF-inhibiting antibody inhibited the production of CD14 + /HLA-DR-MDSCs stimulated by glioma-conditioned media (GCM) in their experimental models [ 36 ].…”

The Gut Microbiota, Kynurenine Pathway, and Immune System Interaction in the Development of Brain Cancer

“…Following immature myeloid cells generation in bone marrow, they are released for their subsequent differentiation into mature myeloid cell, i.e., dendritic cells, macrophages, or granulocytes in peripheral organs. Unlike in a steady state, a partial inhibition in the differentiation of immature myeloid cells into mature myeloid cells occurs during various pathological conditions including cancer, and to a significantly lesser extent, infection, inflammation, sepsis, and trauma (Gabrilovich and Nagaraj, 2009;Raychaudhuri et al, 2015;Alban et al, 2019). These diseases expand MDSC in the circulatory system of patients by modifying STAT3 and Janus protein family members (Bromberg, 2002).…”