Invited ReviewTumor infiltrating immune cells in gliomas and meningiomas
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).
Section snippets
Diagnostic subtypes of glioma and meningioma
CNS tumors are rather heterogeneous and they vary widely by site of origin, morphological and histopathological features, growth potential and extent of invasion. At present, classification of gliomas is mainly based on the existence morphological evidence of differentiation of tumor cells along the astrocytic (70% of the cases) and less frequently the oligodendroglial and mixed astrocytic-oligodendroglial cell lineages in addition to ependymal tumors (Louis et al., 2007). The specific cell(s)
The CNS microenvironment in brain tumors
The CNS has unique microenvironmental conditions which as a whole, differ significantly from most other organs and tissues. To a certain extent, this relates to an active blood brain barrier (BBB), that confers a selective permeability around most CNS blood vessels (Huang et al., 2014, Abbott et al., 2010); such selective permeability, limits diffusion of molecules from the blood to the tissue, limiting the exposure of the brain parenchyma to circulating antigens and metabolites. The BBB
CNS resident immune cells
In the healthy CNS, there are several different subsets of myeloid cells which reside in the brain and other CNS tissues. Thus, parenchymal microglial cells are considered to be CNS resident macrophages (Derecki et al., 2014, Prinz et al., 2014). Myeloid cells which populate other brain compartments are generally referred to as macrophages, prefixed with their localization, e.g. choroid plexus, meningeal or perivascular macrophages (Johnson et al., 2012). Phenotypically, the distinction between
The cellular composition of the cerebrospinal fluid
In recent years, several reports have provided detailed information about the composition of human cerebrospinal fluid (CSF) as regards its immune cell components (Kowarik et al., 2014, Quijano et al., 2009, van Dongen et al., 2012). Overall, CSF is a paucicellular sample which mainly contains leukocytes typically at counts below 5 cells/μL. Around two-thirds of the whole CSF white blood cell populations correspond to T cells (mainly CD4+ and to a less extent also CD8+ T-lymphocytes) and around
Immune cell infiltrates in brain tumors
Several distinct subtypes of immune cells have been reported to infiltrate brain tumors, where they have been associated with a wide spectrum of functions (Wainwright et al., 2012). From the different subtypes of brain tumors, GBM is among the most investigated ones, due to its relatively high incidence and aggressive clinical behavior. Overall, these studies have shown that despite the presence of immune cells in GBM, the overall tumor environment is highly immunosuppressive. In this section
Concluding remarks
At present it is well-established that tumor-infiltrating immune cells play a very important role in tumor development and control. Current efforts focused on the identification and characterization of those immune cells present within the tumor have brought significant insight into the understanding of their effects on tumor behavior, at the same time they have opened new therapeutic pathways (Okada et al., 2011, Hoepner et al., 2013). However, individual tumors may show unique immune profiles
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work was partially supported by the following grants: PIC/IC/83108/2007 from the Fundação para a Ciência e Tecnologia (FCT, Portugal); RD12/0036/0048 from the Instituto de Salud Carlos III (ISCIII/FEDER), Ministerio de Sanidad y Consumo, Madrid, (Spain); GRS689/A/11 & GRS909A14 from the Consejeria Sanidad, Junta de Castilla y León (Spain) and; IB1405 from the Instituto Biosanitario de Salamanca (IBSAL), Salamanca (Spain). Patrícia Domingues was supported by a grant (SFRH/BD/64799/2009)
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