Tumor infiltrating immune cells in gliomas and meningiomas

Highlights

• The presence of tumor infiltrates by immune cells has been reported in both gliomas and meningiomas.

• Tumor-infiltrating immune cells play a very important role in tumor development and control.

• Macrophages predominate over CD8⁺ T-cells in association or not with natural killer- and B-lymphocytes.

• Flow cytometry has been used for the identification and characterization of cell populations in tumor samples.

Abstract

Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors–gliomas and meningiomas–, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control.

Introduction

Tumor development and growth typically requires an appropriate microenvironment, in addition to genetic/molecular alteration of tumor cells. Such tumor microenvironment consists of a complex network of distinct cell types and extracellular matrix components, in which neoplastic cells interact with fibroblasts, vascular endothelial cells, a variety of infiltrating immune cells (including a network of cytokines and chemokines released by these cells) and extracellular matrix proteins, among other components. Although tumor development and growth largely depend on an adequate microenvironment, the tumor cells per se also induce significant changes in the tissue where they home and grow (Whiteside, 2008). Because of this, patients may show behavioral changes including neuropsychiatric symptoms and/or cognitive effects depending on the affected region of the brain and/or the local immune response (Taphoorn and Klein, 2004).

Immune cells present in the tumor typically include T lymphocytes, natural killer (NK) cells, macrophages, dendritic cells (DC), polymorphonuclear leukocytes and occasional B cells (Whiteside, 2008, Fridman et al., 2012). Overall, infiltration by immune cells is a hallmark of virtually every tumor (Quail and Joyce, 2013), and it is frequently associated with tumor behavior and patient outcome (Fridman et al., 2012). In this regard, while multiple reports in the literature have linked the presence of inflammatory infiltrates in human tumors with an improved prognosis and a better patient outcome (Fridman et al., 2012, Pages et al., 2009, Mahmoud et al., 2011), many others have found no significant association, or they have even linked immune cell infiltration with a poorer prognosis (Fridman et al., 2012). Such apparent discrepancy may be due to the type and functional state of immune cells infiltrating the tumor. In fact, the different types of infiltrating immune cell populations vary not only according to the type of cancer, but also from patient to patient within the same type of tumor or at different time points within a patient (e.g. at diagnosis vs. recurrence); these observations suggest that different immune cell microenvironments may have distinct effects/roles in tumor control and progression (Fridman et al., 2012). In addition, the same immune cells present in the tumor microenvironment may modulate their anti-or pro-tumoral functions, being able to play dual roles with potential to either suppress or promote malignancy (Shiao et al., 2011);usually, the latter predominates as the tumor cells acquire mechanisms for ‘immune evasion’. Thus, in such circumstances the tumor, not only manages to escape from the host immune system, but it also develops a phenotype capable of manipulating immune cells (e.g. via secretion of chemokines and cytokines), and modifying their function to create a microenvironment that would favor tumor progression (Mantovani et al., 2008). To date, many mechanisms of immune evasion by tumor cells have been identified (Table 1), including inhibition of immune cell functions or apoptosis of anti-tumor effector cells, together with production of both growth factors and angiogenic factors that stimulate tissue repair and vascularization, and consequently also, tumor growth (Whiteside, 2008). In case of CNS tumors, immune responses may also contribute to induce changes in patient symptoms and behavior, depending on tumor localization and the specific types of immune cells and mediators involved. In this regard, it is considered that younger patients presenting with acute signs and symptoms of neurologic disease are investigated earlier, and consequently, referred more promptly for treatment (Yuile et al., 2006). Conversely, patients with organic brain lesions in neurologically silent brain areas might present with milder symptoms and/or isolated psychiatric symptoms such as depression, anxiety disorders, schizophrenia, anorexia nervosa, or cognitive dysfunction (Cheema et al., 2010, Bunevicius et al., 2008). In such later cases, differential diagnosis between a brain tumor vs. a psychiatric disorder is required, final diagnosis being frequently delayed for variable periods of time (Taphoorn and Klein, 2004, Gehring et al., 2009).