Immune Cell Infiltrates in the Central Nervous System Tumors

Review Article

Austin Neurosurg Open Access.2015;2(1): 1024.

Immune Cell Infiltrates in the Central Nervous System Tumors

Andrew S. Jack¹ and Jian-Qiang Lu²*

1Department of Surgery, University of Alberta Hospital,Canada

2Department of Laboratory Medicine and Pathology,University of Alberta, Canada

*Corresponding author: Jian-Qiang Lu, Department of Laboratory Medicine and Pathology, University of Alberta, 5B2.24 WCM Health Sciences Centre, 8440-112 Street, Edmonton, Alberta T6G 2B7, Canada

Received: March 31, 2014; Accepted: March 01, 2015; Published: March 05, 2015


Major therapeutic advances resulting in overall survival increase have not been forthcoming for most Central Nervous System (CNS) tumors, such as high-grade gliomas. Over the past few decades, our understanding of CNS tumor development has greatly increased due to the introduction of new study techniques particularly in immunohistochemistry and molecular biology. These techniques have aided in the discovery and characterization of tumor-immune cell infiltration. More specifically, the infiltration of CNS tumors by immune cells, such as macrophages/microglia, lymphocytes, and eosinophils has been found to play an important role in tumor pathogenesis and progression. Increased understanding of this tumor immune microenvironment has led to the investigation and trial of immunotherapeutic agents in attempt to modulate the patient immune system and promote an anti-tumor response. In this review, we outline the current state of tumor-immune system interaction research by focusing on the latest evidence for CNS tumor-immune cell infiltration, including macrophages, lymphocytes, and eosinophils. Furthermore, immune cell interaction with the blood-brain barrier leading to infiltration and selected immunotherapeutic strategies are reviewed.

Keywords: Tumor immune microenvironment; Tumor infiltrating lymphocytes (TILs); Glioma associated macrophages/microglia (GAMs); Tumor associated tissue eosinophila (TATE); CNS tumors; Glioblastoma; Immunotherapy


The advent and development of new molecular biological techniques has allowed the investigation and detail of different Central Nervous System (CNS) tumors. All tumors, including benign and malignant CNS tumors, have two basic components: (1) the parenchyma, made up of proliferating neoplastic cells, and (2) the supporting, host-derived, non-neoplastic stroma, made up of connective tissue, blood vessels, and host-derived inflammatory or immune cells [1]. The parenchyma of the neoplasm largely determines its biologic behavior, while the stroma is crucial to the growth of the neoplasm. Stromal cells, particularly infiltrating immune cells and neoplastic cells, carry on a two-way conversation that influences the growth of the tumor. For many malignant tumors there has yet to be a large breakthrough with respect to treatments yielding improved overall survival. For example, glioblastoma (formerly glioblastoma multiforme, GBM), the most prevalent primary malignant CNS tumor, is among the most fatal types of cancer harboring a uniformly dismal prognosis. With minor improvements in median overall survival over the past decade, more effective treatment modalities are required. Although perhaps not a new technique [2-4], the utilization of the body’s natural defense mechanisms through immunotherapy may herald such a breakthrough in tumor treatment. Increased understanding of brain tumor pathophysiology and its interaction with the patient immune system have revealed several immunotherapeutic targets of clinical relevance [5]. In this review, we focus on immune cell infiltration of CNS tumors and its clinical implications. More specifically, we will discuss infiltrating macrophages/microglia, lymphocytes, and eosinophils in the CNS tumor microenvironment.

Neuro-immunological separation, not isolation

Early studies such as those by Medawar et al. initially led to the long-held belief that CNS was an immunologically privileged site in the body [6]. This notion supported other experimental work showing that the allotransplantation of neoplasms was able to escape immunesurveillance that would normally elicit a robust immunological response [7,8]. The CNS also lacks traditional connections to the lymphatic system [9], and is separated from the intravascular space by the Blood-Brain Barrier (BBB) . However, it is now known that the immune system plays an integral role in the etiology and pathophysiology of many CNS diseases [10,11]. The CNS may be separate, but not necessarily isolated from the immune system. For example, when CNS injury occurs, leukocytic infiltration has been proposed as trafficking into the CNS via three mechanisms [12,13]: i) through choroid plexus capillaries into the CSF, ii) through blood into the subarachnoid space, and iii) from blood into the parenchyma. Here, we review how systemic immune cells may penetrate into the CNS parenchyma.

The BBB is one of the key components responsible for separating the CNS extracellular space from the cardiovascular system and its potentially deleterious agents (with the exception of capillaries of the circumventricular organs). The BBB is a selectively permeable barrier, which is composed of the cerebrovascular endothelial cells with characteristic tight intercellular junctions, pericytes, and astrocytic end-feet that make up the glia limitans. Those astrocytes ensheath blood vessels at the one end and at the other end communicate with neuronal processes in formation of a functional unit, the gliovascular unit, which plays a prominent role in maintaining hemostasis of the BBB [14]. Disturbances in this unit may seriously damage the BBB. Moreover, the BBB is not necessarily uniform in structure throughout every segment of the cerebrovasculature. For example, post-capillary venules contain a lower density of tight junctions [15,16] surrounded by a perivascular space. The astrocytic end-feet are also separated here from the endothelial cell wall by up to three basement membrane layers [15,17]. It is here, in the post-capillary venules, that leukocytes will preferentially migrate into the perivascular space [17-19]. The pericyte and vascular endothelial cell coordination helps to regulate this process. The communication between the two cell types requires cytokines such as Platelet-Derived Growth Factor-B (PDGF-B) and transforming growth factor-β (TGF- β) [17,20] which results in decreased CNS immune cell infiltration [21].

Bechmann et al. classified these differentially regulated steps as i) leukocyte passage across post-capillary venules into Virchow-Robin spaces, and ii) subsequent migration across the glia limitans into the neuropil [15]. There is no definitive model; however, detailing the biomolecular stages of how exactly circulating immune cells cross the BBB into the brain parenchyma. One model consists of a multi-step process, akin to that seen in other extra-cerebral sites, of cells “rolling, sticking, and then migrating” [22,23]. Lymphocytes will first slow in the capillary lumen by transiently binding to endothelial cell surface receptors through selectin glycoproteins [24]. This in turn activates more permanent binding between lymphocytes and the vessel wall via integrin glycoproteins, and ultimately results in trans- or paracellular endothelial leukocytic migration [25]. The vasculature found within a tumor’s microenvironment is substantially different from what is found in normal parenchyma. The BBB may be deficient in many areas due to abnormalities found pertaining to the endothelial cell wall, its tight junctions, and basement membrane [26]. The “blood-tumor barrier” has been thought to be more porous than the intact BBB. Abnormal immune cell trafficking may also be associated with the invasion of the capillary wall endothelial cells by tumor cells, possibly disrupting molecules that critical for cellular homing [12]. As a result, it is unclear as to whether the intra-tumoral dysfunctional capillaries would result in increased or decreased immune cell infiltration. Investigation of abnormal brain tumor vasculature has led to the identification of tumor capillaries as a potential immunotherapeutic target. The use of Vascular Endothelial Growth Factor (VEGF) antibodies has been shown to recondition the immunosuppressive tumor microenvironment and shift the expression of immune cell infiltrates toward an anti-tumor phenotype [27].

After migrating through the endothelial cell wall into the perivascular space, parenchymal infiltration becomes another issue. In order to cross the glia limitans, signaling pathways mediated by chemokines such as Monocyte Chemoattractant Protein (MCP)-1 and the expression of Matrix Metalloproteinase (MMP) are thought to be required [15]. Although the mechanisms underpinning the second step of leukocytic migration into the neuropil may not be well understood, an inflammatory reaction is thought to result in astrocytic end-feet retraction, degeneration, and allow for this breach to occur. Furthermore, as previously mentioned, the intra-tumoral BBB is dysfunctional in many areas which may extend into the glia limitans. Inflammatory/immune cell infiltration and homing toward CNS tumors may be then simply a product of chemokine and cytokine signaling, as outlined for astrocytic tumors by Bajetto et al. who have found the expression of multiple CXC chemokines in the brain tumors [28].

Macrophages and Microglia

Macrophages and microglia are derived from monocytes after myelocytic cell differentiation. One of their main functions is as a professional Antigen-Presenting Cell (APC) that triggers an adaptive immune response. They act to clean up cellular and pathogenic debris through phagocytosis, and are intricately involved in the inflammatory process. Microglia are thought to be the resident CNS macrophages acting as an APC, although it is still unclear as to whether or not they elicit a similar response [29]. Although their exact function is still somewhat ambiguous, it is clear that macrophages and microglia make up the primary component of immune cell infiltrates in CNS tumors particularly astrocytic tumors [30]. Table 1 lists the recent studies (using the relatively specific and clinical commonly used immunohistochemical markers) that demonstrate infiltrating CD68+ macrophages/microglia in astrocytic tumors [31-36].

Citation: Jack AS and Lu JQ. Immune Cell Infiltrates in the Central Nervous System Tumors. Austin Neurosurg Open Access.2015;2(1): 1024.