Immune Microenvironment in Glioblastoma Subtypes.
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ABSTRACT:
SUBMITTER: Chen Z
PROVIDER: S-EPMC5951930 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Immune Microenvironment in Glioblastoma Subtypes.
Chen Zhihong Z Hambardzumyan Dolores D
Frontiers in immunology 20180508
Glioblastomas (GBMs) are the most common and aggressive primary brain tumors. Due to their malignant growth and invasion into the brain parenchyma coupled with resistance to therapy, GBMs are among the deadliest of all cancers. GBMs are highly heterogeneous at both the molecular and histological levels. Hallmark histological structures include pseudopalisading necrosis and microvascular proliferation. In addition to high levels of intratumoral heterogeneity, GBMs also exhibit high levels of inte ...[more]
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Project description:BackgroundGlioblastoma-associated macrophages and microglia (GAMs) are the predominant immune cells in the tumor microenvironment. Activation of MerTK, a receptor tyrosine kinase, polarizes GAMs to an immunosuppressive phenotype, promoting tumor growth. Here, the role of MerTK inhibition in the glioblastoma microenvironment is investigated in vitro and in vivo.MethodsEffects of MRX-2843 in glioblastoma microenvironment regulation were determined in vitro by cell viability, cytokine array, in vitro tube formation, Western blotting, and wound healing assays. A syngeneic GL261 orthotopic glioblastoma mouse model was used to evaluate the survival benefit of MRX-2843 treatment. Multiplex fluorescent immunohistochemistry was used to evaluate the expression of CD206, an anti-inflammatory marker on GAMs, and angiogenesis in murine brain tumor tissues.ResultsMRX-2843 inhibited cell growth and induced apoptosis in human glioblastoma cells and decreased protein expression of phosphorylated MerTK, AKT, and ERK, which are essential for cell survival signaling. Interleukin-8 and C-C motif chemokine ligand 2, the pro-glioma and pro-angiogenic cytokines, were decreased by MRX-2843. Decreased vascular formation and numbers of immunosuppressive (CD206+) GAMs were observed following MRX-2843 treatment in vivo, suggesting that in addition to alleviating immunosuppression, MRX-2843 also inhibits neoangiogenesis in the glioma microenvironment. These results were supported by a prolonged survival in the syngeneic mouse orthotopic GL261 glioblastoma model following MRX-2843 treatment.ConclusionOur findings suggest that MRX-2843 has a therapeutic benefit via promoting GAM polarization away from immunosuppressive condition, inhibiting neoangiogenesis in the glioblastoma microenvironment and inducing tumor cell death.
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