Cancer Stem Cell-Secreted Macrophage Migration Inhibitory Factor Stimulates Myeloid Derived Suppressor Cell Function and Facilitates Glioblastoma Immune Evasion

Abstract

Shifting the balance away from tumor-mediated immune suppression toward tumor immune rejection is the conceptual foundation for a variety of immunotherapy efforts currently being tested. These efforts largely focus on activating antitumor immune responses but are confounded by multiple immune cell populations, including myeloid-derived suppressor cells (MDSCs), which serve to suppress immune system function. We have identified immune-suppressive MDSCs in the brains of GBM patients and found that they were in close proximity to self-renewing cancer stem cells (CSCs). MDSCs were selectively depleted using 5-flurouracil (5-FU) in a low-dose administration paradigm, which resulted in prolonged survival in a syngeneic mouse model of glioma. In coculture studies, patient-derived CSCs but not nonstem tumor cells selectively drove MDSC-mediated immune suppression. A cytokine screen revealed that CSCs secreted multiple factors that promoted this activity, including macrophage migration inhibitory factor (MIF), which was produced at high levels by CSCs. Addition of MIF increased production of the immune-suppressive enzyme arginase-1 in MDSCs in a CXCR2-dependent manner, whereas blocking MIF reduced arginase-1 production. Similarly to 5-FU, targeting tumor-derived MIF conferred a survival advantage to tumor-bearing animals and increased the cytotoxic T cell response within the tumor. Importantly, tumor cell proliferation, survival, and self-renewal were not impacted by MIF reduction, demonstrating that MIF is primarily an indirect promoter of GBM progression, working to suppress immune rejection by activating and protecting immune suppressive MDSCs within the GBM tumor microenvironment.

Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases

“…Cancer stem cells produce high levels of macrophage migration inhibitory factor (MIF), which increases the production of the immune suppressive enzyme arginase-1 in MDSCs in a CXCR2 dependent manner. Inhibition of MIF receptor, CXCR2 by antibody decreased production of arginase-1 and thus, blocked immune evasion of tumor cells 349. Inhibition of programmed death-1 (PD-1) by anti-PD-1 antibody prevented tumor growth during early phase tumor progression, but delayed treatment with anti-PD-1 therapy showed little benefits 346.…”

Myeloid-derived suppressor cells in gliomas

“…Macrophage migration inhibitory factor (MIF), which was produced at high levels by glioma stem-like cells (CSCs), increased the expression of the arginase-1 in MDSCs in a receptor Cxcr2-dependent manner. Reduction of MIF conferred a survival advantage to tumour-bearing animals and increased the cytotoxic T cell response towards the tumour [70]. M-MDSCs of GBM patients have increased levels of intracellular S100A8/9 and serum levels compared with M-MDSCs in healthy controls.…”

Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells

“…Multiple other cancers have faced similar obstacles to effective treatment, but this has been recently overcome with the use of immune-modulating therapies, and as a consequence, there is interest in trying to modify the immune system in GBM. Several immunomodulatory approaches are currently under clinical evaluation, including the use of immune checkpoint inhibitors, oncolytic viruses, dendritic cell vaccines, and CAR-T cell approaches 10 , but the wellappreciated immunosuppressive nature of GBM has proven difficult to overcome [11][12][13][14][15] .…”