Abstract
BackgroundInnate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM).MethodsGIM were isolated by sequential Percoll purification from patient tumors immediately after surgical resection. Flow cytometry, phagocytosis and tumor cytotoxicity assays were used to analyze the phenotype and function of these cells.ResultsGIM expressed significant levels of Toll-like receptors (TLRs), however they do not secrete any of the cytokines (IL-1β, IL-6, TNF-α) critical in developing effective innate immune responses. Similar to innate macrophage functions, GIM can mediate phagocytosis and non-MHC restricted cytotoxicity. However, they were statistically less able to mediate tumor cytotoxicity compared to microglia isolated from normal brain. In addition, the expression of Fas ligand (FasL) was low to absent, indicating that apoptosis of the incoming lymphocyte population may not be a predominant mode of immunosuppression by microglia.ConclusionWe show for the first time that despite the immunosuppressive environment of human gliomas, GIM are capable of innate immune responses such as phagocytosis, cytotoxicity and TLR expression but yet are not competent in secreting key cytokines. Further understanding of these innate immune functions could play a critical role in understanding and developing effective immunotherapies to malignant human gliomas.
Highlights
Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain
The data plot on the left indicates the isotype control, and the second plot represents CD45+ gated cells that expressed the respective Toll-like receptors (TLRs). These data are from one tumor specimen but are representative of at least five tumor tissue samples from human glioma patients
Purity of microglia isolated from human gliomas To determine the purity of our gliomainfiltrating microglia (GIM) isolation, cells were stained with fluorescent-labeled antibodies to CD11b, The average yield of microglia isolated from human GBM was 3.2 × 106 cells per gram of tumor but was only 1.4 × 105 cells per gram of normal brain
Summary
Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. Malignant gliomas are the most common type of primary brain tumors and glioblastoma multiforme accounts for more than 50% of all intracranial gliomas [1]. These tumors are extremely aggressive and are characterized by diffuse infiltration of the brain parenchyma, recurrent growth, and an extremely poor prognosis for survival. Immune impairments have been identified within the adaptive arm, few studies have examined for potential deficits in the innate arm, especially within the context of immunosuppressed glioma patients
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