Abstract
OBJECTIVE: To study the importance of myeloid-derived suppressor cells (MDSC) in primary glioblastomas, we investigated the frequency, phenotype, and immune-suppressive function of different myeloid-derived cells (MDC) in the blood and freshly resected tumors of 40 patients. RESULTS: Multicolour flow cytometric analysis showed that the frequency of CD14lowCD15+ granulocytic CD11bhighCD33b+ MDC was higher in peripheral blood and tumor samples of glioblastoma patients compared to healthy controls and positively correlated with the tumor volume before resection. Granulocytic MDC expressed CD16, CD66b, CD114, CD195 and could be further divided into CD14lowCD15high neutrophilic and CD14lowCD15int eosinophilic MDC. Moreover, we could detect an intratumoral accumulation of CD14highCD15+ monocytic CD11bhighCD33b+ MDC expressing CD115, CD124, CD184, CD206 and CX3CR1. All MDC subsets stained positively for reactive oxygen species, but Arginase 1 was specifically expressed in tumor-infiltrating MDC. T cell suppression assays with FACS-sorted MDC revealed that granulocytic and most prominently eosinophilic MDC obtained from the blood, but not the tumor could efficiently suppress non-specific T cell proliferative responses. Contrary to blood-derived MDC, HLA-DR expression was significantly increased on tumor-infiltrating MDC. Upon LPS or R848 stimulation, blood-derived MDC showed an increased production of IL-10, in contrast to tumor-infiltrating MDC that were resistant to Toll-like-receptor (TLR) stimulation. Although the frequency of granulocytic MDC inversely correlated with CD4+ and CD8+ T memory cells in the blood, no association with time to tumor progression in glioblastoma patients could be found. CONCLUSION: Our findings provide a detailed characterization of the nature and suppressive function of MDC in glioblastoma patients and indicate that granulocytic MDC obtained from the blood but not from the tumor mainly suppress T-cell proliferation.
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