The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses1

Abstract

Little is known about the immune performance and interactions of CNS microglia/macrophages in glioma patients. We found that microglia/macrophages were the predominant immune cell infiltrating gliomas ( approximately 1% of total cells); others identified were myeloid dendritic cells (DCs), plasmacytoid DCs, and T cells. We isolated and analyzed the immune functions of CD11b/c+CD45+ glioma-infiltrating microglia/macrophages (GIMs) from postoperative tissue specimens of glioma patients. Although GIMs expressed substantial levels of Toll-like receptors (TLRs), they did not appear stimulated to produce pro-inflammatory cytokines (tumor necrosis factor alpha, interleukin 1, or interleukin 6), and in vitro, lipopolysaccharides could bind TLR-4 but could not induce GIM-mediated T-cell proliferation. Despite surface major histocompatibility complex class II expression, they lacked expression of the costimulatory molecules CD86, CD80, and CD40 critical for T-cell activation. Ex vivo, we demonstrate a corresponding lack of effector/activated T cells, as glioma-infiltrating CD8+ T cells were phenotypically CD8+CD25-. By contrast, there was a prominent population of regulatory CD4 T cells (CD4+CD25+FOXP3+) infiltrating the tumor. We conclude that while GIMs may have a few intact innate immune functions, their capacity to be stimulated via TLRs, secrete cytokines, upregulate costimulatory molecules, and in turn activate antitumor effector T cells is not sufficient to initiate immune responses. Furthermore, the presence of regulatory T cells may also contribute to the lack of effective immune activation against malignant human gliomas.

The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas

“…This finding is interesting because it differs from all imaging studies with [ 11 C](R)-PK11195 [11], microarray studies [5], studies in vitro [27,28], animal model [3,29,30] and post-mortem brains [22] that showed high expression of PBR in activated microglia in a variety of inflammatory, degenerative, infective and vascular CNS disorders. Our approach of combining the evaluation of PBR using [ 11 C](R)-PK11195 PET-scan and immunohistochemistry offered the advantage of studying the binding capacity of this molecule in vivo and, on tissues its distribution in the cell types constituting the two astrocytomas without the changes that may occur examining microglia in vitro, outside the complexity of interactions with other cell types [5]. In addition, these two cases represented a rare opportunity and an excellent model to investigate microglial PBR because they showed low-PBR expression in neoplastic cells and minimal contrast enhancement indicating minimal disruption of the blood brain barrier and therefore little presence of blood-borne macrophages within tumour tissue.…”

“…These findings elicit an intriguing hypothesis on the role of PBR in microglial immune functions. The PBR is one of the most common molecules expressed by microglial cells during activation but its role in these cells is unknown and the molecular pathway linking the functions of PBR to microglial response has not been elucidated [5]. In a mouse model, Banati et al [42] showed that PBR is up-regulated at the early stages of activation when microglial cells still show a ramified morphology and suggested that PBR may be a key molecule in microglial immune response.…”

“…Activation can be triggered by a broad variety of stimuli including hypoxia, accumulation of insoluble molecules, infective agents or the contact with neoplastic cells [4]. In anaplastic astrocytomas and glioblastomas, microglia contribute significantly to the total tumour mass but the fact that neoplastic cells manage to survive and grow in their presence indicate the failure of normal defence mechanisms [5,6]. The causes of poor microglial response to tumour cells are still unclear although recent studies have demonstrated glioma-infiltrating microglial cells show an impairment of antigen presenting functions [6][7][8][9][10].…”

“…The peripheral benzodiazepine receptor (PBR) is one of the earliest and most commonly expressed molecules during microglial activation in inflammatory, degenerative, vascular and infective CNS diseases [3,5,11]. For this reason, high levels of PBR are generally considered a marker of microglial activation [5], and the PBRspecific ligand [ 11 C](R)-PK11195 is widely used in positron emission tomography (PET) studies to trace microglial infiltrate as an in vivo indicator of tissue damage [11].…”

“…For this reason, high levels of PBR are generally considered a marker of microglial activation [5], and the PBRspecific ligand [ 11 C](R)-PK11195 is widely used in positron emission tomography (PET) studies to trace microglial infiltrate as an in vivo indicator of tissue damage [11]. Also known as PK-11195 binding protein or translocator protein, the PBR is an 18 kDa molecule consisting of a five helices spanning the membrane lipid bilayer of the outer mitochondrial membrane and forming a heterotrimer together with a voltage dependent anion channel and an adenine nucleotide transporter [12,13].…”