Abstract
BackgroundSystemic and local immune suppression plays a significant role in glioma progression. Glioma microenvironment contains both brain-resident microglial cells (MG) and bone marrow-derived macrophages (BMDM), but the study of their functional and immune regulatory activity has been hampered until now by the lack of markers allowing a proper identification and isolation to collect pure populations.MethodsMyeloid and lymphoid infiltrate were characterized in grade II, III and IV gliomas by multicolor flow cytometry, along with the composition of the cell subsets of circulating myeloid cells. Macrophages were sorted and tested for their immunosuppressive ability. Moreover, following preoperative administration of 5-aminolevulinic acid to patients, distinct areas of tumor lesion were surgically removed and analyzed, based on protoporphyrin IX fluorescence emission.ResultsThe immune microenvironment of grade II to grade IV gliomas contains a large proportion of myeloid cells and a small proportion of lymphocytes expressing markers of dysfunctional activity. BMDM and resident MG cells were characterized through a combination of markers, thus permitting their geographical identification in the lesions, their sorting and subsequent analysis of the functional characteristics. The infiltration by BMDM reached the highest percentages in grade IV gliomas, and it increased from the periphery to the center of the lesion, where it exerted a strong immunosuppression that was, instead, absent in the marginal area. By contrast, MG showed little or no suppression. Functional differences, such as iron metabolism and phagocytosis, characterized resident versus blood-derived macrophages. Significant alterations in circulating monocytes were present in grade IV patients, correlating with accumulation of tumor macrophages.ConclusionsGrade IV gliomas have an alteration in both circulating and tumor-associated myeloid cells and, differently from grade II and III gliomas, show a significant presence of blood-derived, immune suppressive macrophages. BMDM and MG have different functional properties.
Highlights
The concept of the immune privilege of the central nervous system (CNS) has recently been revised and it appears that local immunity can adapt to a peculiar environment, directed by a flexible blood brain barrier and by the presence of unconventional lymphatic vessels [1, 2]
Elegant genetic mouse models have demonstrated that bone marrow-derived macrophages (BMDM) and microglial cells (MG) are both present in gliomas and possess distinct transcriptional and chromatin states [6], and that during GBM growth there is an influx of myeloid cells in the tumor microenvironment [3, 7], which represents the main source of tumor-infiltrating macrophages
BMDM infiltration in GBM tissues is sustained by circulating monocytes Since immunosuppressive macrophages that infiltrate GBM are blood-derived, we investigated the characteristics of circulating monocytic cells in the same patients and, as previously reported [7, 27], observed a higher percentage of circulating monocytes compared to a group of age and gender matched healthy donors (HD) (Fig. 6a)
Summary
The concept of the immune privilege of the CNS has recently been revised and it appears that local immunity can adapt to a peculiar environment, directed by a flexible blood brain barrier and by the presence of unconventional lymphatic vessels [1, 2]. Local immunity in the CNS is completely subverted by a growing tumor, as documented by the presence of a leukocyte infiltrate in different brain tumors [3] Another peculiarity of the CNS is the presence of microglia (MG) cells, resident macrophages fulfilling the role of immune surveillance and removal of debris, with a distinct ontogenesis compared to bone-marrow derived macrophages (BMDM) that heavily infiltrate tumors [4, 5]. Systemic and local immune suppression plays a significant role in glioma progression Glioma microenvironment contains both brain-resident microglial cells (MG) and bone marrow-derived macrophages (BMDM), but the study of their functional and immune regulatory activity has been hampered until now by the lack of markers allowing a proper identification and isolation to collect pure populations
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