Eosinophils in glioblastoma biology

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review.

Figure 1

The immune response in cancer and atopic disease. (1) Full activation of antigen presentation cells (APCs: e.g. Dendritic cell, B cell) and T cells. (2) T cell cytokines (IL-4, IL-13) and soluble CD23 ligation to CD21, induces B cell differentiation, the generation of plasma cells, the production of IgE, and the subsequent IgE-dependent activation of mast cells. (3) Activated mast cells, APCs, and T cells produce chemokines and cytokines that recruit granulocytic cells (eosinophils, macrophages, neutrophils). (4) Immuno-suppressive cytokines (IL-10, TGF-β) are produced by tumor cells, suppressor macrophages, and T regulatory (CD4+ Treg) cells. These cytokines and additional mediators or cell:cell interactions prevent a specific adaptive immune response required in tumor eradication (see text for additional details).

Figure 2

The potential role(s) of tumor associated eosinophils. Tumor development has been characterized as proceeding through several stages (initiation, promotion, progression). The initiation stage is a period of mutagenesis where genetic and/or epigenetic alternations in stem cells or progenitor cells are established. The promotion stage invokes cellular growth (mitogenesis) that is induced by growth factors and altered apoptotic cell signal pathways. This increased cell division creates a microenvironment of metabolic stress, hypoxia and necrotic cell death that has also been associated with thrombosis. The progression stage involves additional genetic and epigenetic events that confer phenotypic changes necessary for tumor cell autonomous growth, invasiveness, and migration. Eosinophils are able to produce growth factors, cytokines, chemokines, blood coagulants, and cytotoxic mediators that may affect each stage of tumor development.

Figure 3

Eosinophils in tumor promotion. A microenvironment involving rapidly dividing cells induces tumor necrosis and the production of damage associated molecular patterns (DAMPs) which include the RAGE ligands (e.g.: HMGB1 and S100 proteins). Eosinophils and additional innate immune cells (microglia, mast cells, neutrophils) are activated by GBM mediators (GM-CSF, PDGF, CXCL12, CXCL8) and DAMPs which may in turn induce the production of growth factors (amphiregullin, TGF-α, VEGF) and matrix metalloproteinases in promoting tumorigenesis. Alternatively, in certain cases, eosinophil release of cytotoxic granules (EDN, ECP, calprotectin) may function to prevent tumor promotion.

Figure 4

GBM innate and adaptive immunity. Cytokines and chemokines produced by tumor cells are indicated to alter the tumor suppressive functions of innate immune cells (natural killer cell, microglia, neutrophil, mast cell) thereby creating a microenvironment that is conducive to tumor development. Immune activators associated with allergy/asthma (IL-4, IL-13, CD23:CD21 ligation, IgE, TLR ligands) induce the recruitment and activation of immune cells (mast cells, eosinophils, natural killer cells, CD8+ T cells), the suppression of CD4+ Treg development, tumor rejection, and enhanced host survival (see text for additional details).