Cerebrospinal fluid cytokine levels are associated with macrophage infiltration into tumor tissues of glioma patients

Abstract

Background Diffuse gliomas are the most common malignant tumors of the central nervous system with poor treatment efficacy. Infiltration of immune cells into tumors during immunosurveillance is observed in multiple tumor entities and often associated with a favorable outcome. The aim of this study was to evaluate the infiltration of immune cells in gliomas and their association with cerebrospinal fluid (CSF) cytokine concentrations. Methods We applied immunohistochemistry in tumor tissue sections of 18 high-grade glioma (HGG) patients (4 anaplastic astrocytoma, IDH-wildtype WHO-III; 14 glioblastomas (GBM), IDH-wildtype WHO-IV) in order to assess and quantify leucocytes (CD45) and macrophages (CD68, CD163) within the tumor core, infiltration zone and perivascular spaces. In addition, we quantified the concentrations of 30 cytokines in the same patients’ CSF and in 14 non-inflammatory controls. Results We observed a significantly higher percentage of CD68+ macrophages (21–27%) in all examined tumor areas when compared to CD45+ leucocytes (ca. 3–7%); CD163+ cell infiltration was between 5 and 15%. Compared to the tumor core, significantly more macrophages and leucocytes were detectable within the perivascular area. The brain parenchyma showing a lower tumor cell density seems to be less infiltrated by macrophages. Interleukin (IL)-7 was significantly downregulated in CSF of GBM patients compared to controls. Additionally, CD68+ macrophage infiltrates showed significant correlations with the expression of eotaxin, interferon-γ, IL-1β, IL-2, IL-10, IL-13, IL-16 and vascular endothelial growth factor. Conclusions Our findings suggest that the infiltration of lymphocytes is generally low in HGG, and does not correlate with cytokine concentrations in the CSF. In contrast, macrophage infiltrates in HGG are associated with CSF cytokine changes that possibly shape the tumor microenvironment. Although results point towards an escape from immunosurveillance or even exploitation of immune cells by HGG, further studies are necessary to decipher the exact role of the immune system in these tumors.

Inflammatory Mediators and GBM Malignancy: Current Scenario and Future Prospective

“…The circulatory levels of inflammatory cytokines show a parallel correlation with the capability of tumor cells to produce pro-inflammatory cytokines, and the role of IL-6 in angiogenesis. At the same time, the IL-6 expression is directly linked to IL-1, IL-8, and interferonγ (IFN-γ) [72]. It has been shown that IL-6 may act as a potential anti-invasion target since it is involved in carcinogenesis by angiogenesis and tumor growth [73].…”

Cytokine Landscape in Central Nervous System Metastases

“…Initially, CSF was considered useful only for maintaining the homeostatic environment necessary for normal brain function. However, in addition to providing an homeostatic environment, CSF is a pathway for signal transmission during neurological development and progression of primary and metastatic brain tumors [81,82].…”

“…Initially, CSF was considered useful only for maintaining the homeostatic environment necessary for normal brain function. However, in addition to providing an homeostatic environment, CSF is a pathway for signal transmission during neurological development and progression of primary and metastatic brain tumors [ 81 , 82 ]. Researchers hypothesized that a group of cytokines and chemokines called immunokines can be detected in the CSF and thus can help as biomarkers in understanding the course of BM.…”

Correlation of tumor-associated macrophage infiltration in glioblastoma with magnetic resonance imaging characteristics: a retrospective cross-sectional study

“…Under different stimuli, macrophages in the tumor microenvironment can be polarized to antitumor (M1) or tumor-promoting (M2) phenotypes. However, most macrophages recruited to the tumor microenvironment become the M2 subtype ( 7 , 8 ). M2 phenotypic macrophages promote tumor cell proliferation, tumor invasion, migration and angiogenesis by secreting extracellular matrix components.…”