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.
Highlights
Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and remains uniformly fatal despite aggressive therapies including surgery, radiation, and chemotherapy [1, 2]
While myeloid-derived suppressor cells (MDSCs) have been linked to GBM prognosis and progression, technical hurdles including the inability for their long-term expansion have been a challenge for mechanistic insight and functional assessment [9, 19, 59]
We found that the receptor CD74 may play a greater role in GBM MDSC biology because the subset of MDSCs primarily found in the tumor microenvironment were monocytic subset of MDSCs (M-MDSCs), which predominantly express CD74 as a migration inhibitory factor (MIF) receptor
Summary
Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and remains uniformly fatal despite aggressive therapies including surgery, radiation, and chemotherapy [1, 2]. Early clinical trials of immune checkpoint therapies in GBM have demonstrated limited response, if any, and despite some evidence of immune cell accumulation, GBM growth persists [7, 8] One explanation for these failures could be the potent immunosuppressive factors present in GBM, including the high tumor content of myeloid-derived suppressor cell (MDSC) [9,10,11,12]. MDSCs in the peripheral circulation and infiltrating in the GBM microenvironment correlated with poor prognosis [9, 19] Based on these observations in GBM and other cancers, attempts to target MDSCs using multiple approaches, including lowdose chemotherapy in a recent GBM trial are in clinical evaluation [20]. These approaches use non-specific strategies that attenuate MDSCs, as opposed to targeted approaches that are MDSC-specific and may have a higher therapeutic utility
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