Clinical Neurology and Neurosurgery 119 (2014) 125–132

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Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro

Review

The role of regulatory T-cells in glioma immunology Yinn Cher Ooi a , Patrick Tran a , Nolan Ung a , Kimberly Thill a , Andy Trang a , Brendan M. Fong a , Daniel T. Nagasawa a , Michael Lim b,c , Isaac Yang a,d,∗ a

Department of Neurosurgery, University of California Los Angeles, Los Angeles, USA Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, USA Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, USA d Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, USA b c

a r t i c l e

i n f o

Article history: Received 30 July 2013 Received in revised form 3 December 2013 Accepted 8 December 2013 Available online 3 January 2014 Keywords: Gliomas Immunology Regulatory T-cells

a b s t r a c t Despite recent advances in treatment, the prognosis for glioblastoma multiforme (GBM) remains poor. The lack of response to treatment in GBM patients may be attributed to the immunosuppressed microenvironment that is characteristic of invasive glioma. Regulatory T-cells (Tregs) are immunosuppressive T-cells that normally prevent autoimmunity when the human immune response is evoked; however, there have been strong correlations between glioma-induced immunosuppression and Tregs. In fact, induction of Treg activity has been correlated with glioma development in both murine models and patients. While the exact mechanisms by which regulatory T-cells function require further elucidation, various cytokines such as interleukin-10 (IL-10) and transforming growth factor-␤ (TFG-␤) have been implicated in these processes and are currently under investigation. In addition, hypoxia is characteristic of tumor development and is also correlated with downstream induction of Tregs. Due to the poor prognosis associated with immunosuppression in glioma patients, Tregs remain a promising area for immunotherapeutic research. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current goals and approaches of glioma immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Normal induction of regulatory T-cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological role of regulatory T-cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathological induction of regulatory T-cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of hypoxia in regulatory T-cell induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The prognosis for glioblastoma multiforme (GBM) remains poor, despite maximal treatment with tumor resection, chemotherapy and radiation. Though gliomas may be immunogenic [1], patients characteristically present with heightened levels of immunosuppression as tumor grade increases [2]. As glioma development and

∗ Corresponding author at: Department of Neurosurgery, University of California Los Angeles, 695 Charles E. Young Drive South, Gonda 3357, Los Angeles 90095-1761, USA. Tel.: +1 310 267 2621/794 5664; fax: +1 310 825 9385. E-mail address: [email protected] (I. Yang). 0303-8467/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2013.12.004

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patient prognosis may be critically dependent upon the immunosuppressed microenvironment in which the tumor resides, factors such as immunosuppressing regulatory T-cells (Tregs) and signal transducer and activator of transcription 3 (STAT3) expression may have significant prognostic implications and represent promising therapeutic targets [3]. The normal human immune response is composed of humoral and cell-mediated responses which function to defend the body against foreign bodies such as bacteria, viruses, and tumors. However, in order to prevent these responses from harming normal cells, the body utilizes Tregs, an endogenous subset of CD4+ T-cells [4–6], to suppress inflammation and maintain self-tolerance [7]. Dysfunction or deficiency of Tregs may elicit autoimmune conditions, such as lupus and arthritis [8], and

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stimulate tumor immunity. Thus, Tregs are currently believed to be a primary regulator of the immunosuppression present in glioma microenvironments [9]. While the exact mechanism of Treg immunosuppression remains unclear, it is proposed that immune inhibition occurs through cell–cell contact with Tregs [10]. These implications may have clinical applications in determining ideal treatments for glioma, allowing Tregs to serve as promising immunotherapeutic targets. Here, we analyze the molecular characteristics, biological role, and inductive mechanisms of Tregs in the normal human immune system and in the presence of GBM. 2. Current goals and approaches of glioma immunotherapy The basic principle of immunotherapy is to evoke a tumorspecific cellular immune response in order to selectively eliminate cancer cells. The efficacy of immunotherapeutic treatments rely on the generation of a sufficient antitumor immune response that is specific, long-lasting, and safe relative to the existing adjuvant therapies of radiation and/or chemotherapy. Currently, several immunotherapeutic approaches are under study for the treatment of GBM – adoptive, passive, and active immunotherapy. Adoptive immunotherapy activates and expands tumor-infiltrating cytotoxic T-cells ex vivo, before administering them to the patient [11]. Passive immunotherapy administers engineered immune effectors such as monoclonal antibodies [12]. Active immunotherapy utilizes the patient’s own immune cells to generate an antitumor response via vaccine administration, countering the immunosuppressive effects of Tregs and other tumor-induced mechanisms. The following are a few active immunotherapies currently being studied (Fig. 1) – peptide-based vaccines, dendritic cell (DC)-based vaccines, and vault nanoparticle vaccines. Peptide-based vaccines consists of glioma-associated antigens (GAAs) or glioma-specific antigens (GSAs) which are processed by antigen presenting cells that go on to activate naive T cells. Dendritic cell-based vaccines are DCs loaded with tumor antigens that go on to prime the patient’s own T-cells to target these tumor antigens. Finally, vault nanoparticle vaccines utilize vaults as delivery vessels for immune activating peptides such as chemokine CCL21 – an effective lung tumor growth inhibitor in murine models [13].

they are induced by pathological conditions such as infection or tumor infiltration [4–6]. Thymic differentiation of T-cells into CD8+ cytotoxic T-cells, CD4+ conventional T-cells, or CD4+CD25+FOXP3+ Tregs is regulated by T-cell receptor (TCR) signaling – in the case of Treg differentiation is controlled by a range of TCR affinity and avidity [24,25]. Tregs can also be derived by inducing FOXP3 expression in CD4+FOXP3− conventional T-cells that have already undergone differentiation in the thymus and migrated into the periphery [26–28]. In vivo, thymic-differentiated Tregs and peripherally induced Tregs show little overlap in TCR recognition [29]. A study by Haribhai et al. showed that in vitro induced Treg with TCR stimulation and TGF-␤ and IL-2 exposure are genetically distinct from in vivo Tregs from murine models, though there are a number of shared genes. It was also found that both thymic and induced Tregs are required for preventing lymphoproliferative disease, suggesting complementary roles for these two Treg subsets [30]. The expression of FOXP3 and its response to stimulation as well as thymus function differs in human and murine models [31–34], therefore studying the in vivo characteristics of Treg and FOXP3 in mice may not be fully relevant to humans. Tregs are often characterized by one or more of the unique surface markers that they express. In addition to CD4+ expression, Tregs may also display CD25 (an interleukin-2 receptor) [4,7], CD38 [35], CD62L [36], CD73 [37], CD127dim, and C127low expression [38]. Other molecular markers that have been found on Tregs include transcription factor forkhead box P3 (FOXP3) [39], glucocorticoid-induced tumor necrosis factor-like receptor (GITR) [40], lymphocyte activation gene 3 [41], and cytotoxic Tlymphocyte associated protein 4 (CTLA-4) [42]. These markers can be utilized to isolate Treg populations and analyze changes in Treg populations in GBM patients [38]. Current research suggests that tumor burden in murine glioma models may initiate an increase in infiltration, proliferation, and survival of Tregs [43]. These cells typically compose 5–15% of peripheral CD4+ T-cells in healthy individuals [44]. However, the Treg fraction of tumor-infiltrating lymphocytes has been shown to increase in both murine models and in as many as 60% of glioma patients, despite a decrease in absolute number of all T-cells [45,46]. While physiologic induction of Treg cells is important for preventing autoimmunity, it may be detrimental in glioma patients when it inhibits the immune system’s ability to fight off infections or tumors.

3. Normal induction of regulatory T-cells In a typical human immune system, infectious challenges induce cellular and humoral immune responses, some of which are capable of causing tissue damage that may harm the body [14]. The dysfunction of mechanisms that prevents the immune system to recognize self and non-self is characteristic of autoimmune disease, and this ultimately leads to auto-destruction by one’s own immune responses [10]. One strategy employed to maintain self-tolerance and prevent collateral tissue damage is mediated by Tregs [15]. These cells are capable of down-regulating antigen-specific T-cell responses that can be responsible for autoimmunity [16] through various processes dependent upon Treg subtype [17]. Levels of circulating Tregs have been shown to be reduced in individuals with a variety of autoimmune diseases, such as juvenile idiopathic arthritis [18], psoriatic arthritis [19], hepatitis C-associated mixed cryoglobulinemia [20], autoimmune liver disease [21], systemic lupus erythematosus [22], and Kawasaki disease [23]. However, the absence of circulating Tregs is not an essential component of all autoimmune diseases, as many do not display this same characteristic [19,22]. Tregs are an endogenous subset of CD4+ T-cells that are differentiated in the thymus from which they migrate to secondary lymphoid organs; these include the spleen and lymph nodes, where

4. Biological role of regulatory T-cells The natural role of Tregs is to prevent the normal human immune response from causing extensive self-tissue damage. Tumors, such as gliomas, utilize this immunosuppressive function of Tregs to evade immune responses. However, the specific mechanisms by which Tregs suppress immunity remains unclear, while studies thus far have revealed only correlations between Treg levels and tumor activity. Severe immunosuppression within the tumor microenvironment is characteristic of gliomas [47], and may suggest a mechanism underlying the poor prognosis of glioblastoma multiforme (GBM). Studies have shown that infiltration of CD4+ and CD8+ T-cells [48] are induced as early as 10 days after intracranial tumor implantation in mice, suggesting normal immune responses. However, CD4+ T-cell levels began to drop at day 15, demonstrating an initial immune response that is quickly followed by T-cell anergy and immunosuppression [49]. Effective T-cell proliferation and function are significantly inhibited even when CD4+ T-cells are isolated and cultured in vitro [50], implying that the immune dysfunctions originate specifically from within the population of CD4+ T-cells [51]. This inhibitory microenvironment suppresses the

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Fig. 1. A few forms of active immunotherapy that are currently being studied today are peptide-based vaccinations, dendritic cell (DC)-based vaccinations, and vault nanoparticle vaccinations. The goals of peptide- and DC-based vaccinations are to stimulate DCs to present glioma-associated antigens (GAAs) or glioma-specific antigens (GSAs) via vaccinations with GSAs/GAAs or DCs already pulsed in tumor lysate. Vault nanoparticles are a novel way to deliver immunogenic peptides, whether it is GSAs/GAAs or chemokines, into the lymphatic system to build a tumor-specific immune response or intratumorally to recruit lymphocytes into the tumor microenvironment. The ideal response to these immunotherapies (as shown) is to activate tumor-specific T-cells and recruit them into the tumor microenvironment in order to lyse tumor cells.

host’s anti-tumor response from the early, asymptomatic stages of tumor invasion [52]. In addition, despite the fact that lymphopenia is often observed in GBM patients in peripheral blood, spleen, and cervical lymph nodes [45], Treg levels remain disproportionately high within the tumor microenvironment. Treg levels in peripheral blood are also increased in GBM patients [38], but they do not increase to the extent of that adjacent to the tumor, suggesting that the lesions themselves may have direct effects on Treg induction [43]. These findings of lymphocytopenia observed in GBM patients may be explained by the studies suggesting that Tregs induce apoptosis and disrupt the proliferation of lymphocytes [53]. Increases in Treg levels have been correlated with inhibition of activity in effective T-cells [41], most likely through cell–cell contact involving CTLA-4 [42]. CTLA-4 binds to CD80 and CD86 on antigen presenting cells, effectively down-regulating effector T-cell activation [54]. In vitro studies have shown that Treg depletion is correlated with a recovery in CD4+ T-cell proliferation and reversal of induced immunosuppressive cytokine secretions. In murine models of implanted glioma, Treg depletion led to tumor rejection [45] and is also correlated to increased survival [4]. Interestingly, studies show that CTLA-4 targeted treatments show improved immune response through stimulated proliferation and resistance to immunosuppressive Tregs in CD4+CD25− T-cells while Treg suppressive functions remain unchanged [55]. CTLA-4 has been shown to be a promising target for cancer treatment [56] as well as a

clinically relevant biomarker for identifying individuals with a high risk of developing glioma [57]. One possible mechanism for Treg function may be that FOXP3 expression in Tregs induces expression of heme oxygenase-1 (HO1) [2]. HO-1 inhibits T-cell proliferation [58], which accounts for the lymphocyte-suppressing features of Tregs. In addition, HO1 expression renders T-cells resistant to Fas-mediated apoptosis [59], which may contribute to the overrepresentation in the CD4+ T-cell population in tumor microenvironments. This immunosuppression elicited by Tregs may allow for tumor growth and evasion of immunosurveillance that would not normally be possible in an immunologically competent microenvironment. The primary targets of Treg inhibition are antigen-presenting cells, such as lymphocytes and DCs [60]. Tregs suppress these cells through down-regulation of interleukin-2 (IL-2) [61], inhibition of Interferon-␥ (IFN-␥) [62], and stimulation of target cells to secrete immunosuppressive cytokines that further induce Tregs [63]. IL2 and IFN-␥ are significant mediators of the immune response by stimulating the activation of both T-cells and DCs, and also through the mediation of myeloid maturation [64,65]. IFN-␥ has also been demonstrated to play a critical role in the induction of indoleamine 2,3-dioxygenase 1 (IDO) [66], an enzyme involved in tryptophan catabolism and mediator of tumor immunosuppression. Another proposed mechanism of Treg-mediated immunosuppression is through the activity of transforming growth factor-␤ (TFG-␤). Studies, however, have shown that TFG-␤ may play a significant role in

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the induction and conversion of Treg, rather than as an effector immunosuppressive cytokine expressed by Tregs [67,68].

5. Pathological induction of regulatory T-cells In murine models, peripheral Tregs have been shown to increase as a response to both primary [69] and metastatic brain tumors [2,40,41,49,70] as early as ten days after tumor implantation [49]. Jacobs et al. examined 83 brain tumor patients demonstrating that the ratio of infiltrating Tregs to CD4+ T-cells is positively correlated with the World Health Organization (WHO) grade of the tumor, with a higher ratio of infiltration correlating with an increased WHO grade [71]. In addition, it has been proposed that tumors may actively promote survival of cells that aid in tumor tolerance [72]. A study by Crane et al. demonstrated that Tregs have reduced expression of pro-apoptotic genes (Bax, Bak, and Bim) when cultured with tumor cell medium, while conventional T-cells increase expression of Bax, Bak, and Bim [43]; this suggests a possible mechanism for preferential Treg survival in tumor microenvironments. Studies have also shown that CD25+FOXP3+ cell levels are prognostically neutral [46], since activated non-regulatory CD4+ T-cells transiently express CD25+FOXP3+ [73,74]. However, despite the relationship between glioma development and Treg infiltration, no correlations were found between Treg levels and tumor volume [71]. In addition to the infiltration of thymic-differentiated Tregs, the conversion of naïve CD4+ T-cells into Tregs has also been shown to occur in animal models [75–78]. This may provide another mechanism in which Tregs are recruited. A study by Crane et al. on the plasticity of T-cells has shown that soluble factors secreted from tumors can convert conventional CD4+ T-cells to functional Tregs, characterized by TGF-␤ and FOXP3+ expression, as well as the ability to suppress conventional T-cell proliferation. However, this effect was only transiently observed, as TGF-␤ and FOXP3+ expression levels returned to normal limits within 10-days of exposure to the tumor-conditioned medium [43]. A study by Wainwright et al. has also found that the population of CD4+FOXP3+ T-cells within brain tumors is predominantly represented by thymusderived Tregs, as opposed to peripheral induced Tregs. This study was performed by comparing brain tumors of mice that had previously been thymectomized against those that had not – results showed that thymectomy significantly decreased tumor infiltration of Tregs [79]. Interestingly, it has been shown that the proliferation of Tregs in the CD4+ T-cells population correlates with increased levels of interleukin-10 (IL-10) [69], an immunoinhibitory cytokine [80]. IL10 is an inhibitor of the CD28 co-stimulatory pathway in T-cells [81,82]. Suppression of this pathway prevents activation of T-cells and cytokine secretion, since their activation requires both stimulation of T-cell receptors in addition to a co-stimulatory signals [81]. One way gliomas regulate Tregs in the tumor microenvironment is through production of TGF-␤. Despite the role of TGF-␤ in converting in vitro CD4+ T-cells into FOXP3+ Tregs and the high expression of TGF-␤ by gliomas [83], Treg populations in brain tumors are predominantly thymus-derived and not peripherally induced Tregs [79]. Though Treg accumulation in the tumor microenvironment could be independent of TGF-␤, studies show that neutralizing TGF-␤ results in a decrease of tumor-infiltrating Tregs – this suggests that TGF-␤ plays some role in the recruitment and/or expansion of Tregs [84]. Recent studies by Wainwright et al. show correlation between upregulated IDO expression with a significant decrease in survival in glioma patients. By examining the effects of IDO-competent tumors in both IDO-competent and deficient mice, Wainwright

et al. found that IDO expression in tumors accumulates immunosuppressive Tregs. These results suggest a significant role of IDO in recruitment of Tregs – possibly via chemokine induction. It has also been shown that IDO-competent brain tumors stimulate infiltrating Tregs to express glucocorticoid-induced tumor necrosis factor-like receptor (GITR) when compared to IDO-deficient tumors [85]. Studies on GITR, a type 1 transmembrane protein highly expressed in Tregs, show evidence that it directly inhibits mediation of responder T-cell suppression [86]. Cohen et al. has shown that an agonist anti-GITR monoclonal antibody (mAb), DTA-1, stimulates GITR and induces tumor regression in murine models. DTA-1 does not appear to affect systemic Treg frequency nor their immunosuppressive activity, although it significantly impairs intratumoral accumulation of Tregs [87]. These results suggest that GITR may be a mediator of Treg recruitment into the brain. Within the brain, however, tumors are shown to promote Treg expression of GITR when compared to Tregs in draining cervical lymph nodes and spleen [88]. Researchers have also proposed that integrins may be a mediator of Treg infiltration since ␣4␤1 integrin plays a key role in facilitating T-cell entry into the brain [52] and ␣E␤7 integrin induction has been linked to retention of CD8+ T-cells at tumor sites [52]. Tran Thang et al. showed that ␣E␤7 integrin is also expressed in up to 40% of CD4+ T-cells and in an average of 71% of brain-infiltrating Tregs. By contrast, ␣E␤7 integrin was poorly expressed in FOXP3CD4+ T-cells and peripheral Tregs [52]. The early induction and infiltration of Tregs, via proposed cytokines, integrins, and naïve T-cell conversion mechanisms, suggest that they may play a key role in generating an immunosuppressed microenvironment that facilitates tumor growth.

6. The role of hypoxia in regulatory T-cell induction GBM development has also been closely associated with local hypoxia due to rapid growth of cells, insufficient neovascularization, irregular blood flow, anemia, and the high oxygen consumption of rapidly growing tumors [89,90]. Hypoxia promotes tumor proliferation by activating the STAT3 immunosuppressive pathway via phosphorylation [91]. Tregs present with elevated activation of STAT3, which further increases Treg proliferation and promotes inhibition of CD8+ T-cell differentiation and DC maturation through expression of FOXP3, TGF-␤, and IL-10 [92,93] (Fig. 1). Pallandre et al. demonstrated that STAT3 is critical in the molecular pathway required for FOXP3 expression, a characteristic Treg marker that has been shown to give CD4+ lymphocytes immunosuppressive functions. Furthermore, inhibition and ablation of STAT3 in CD4+ lymphocytes inhibits FOXP3 expression and suppressive functions while enhancing anti-tumor immunity; these findings suggest a direct role of STAT3 in Treg phenotype and function [94]. Inhibition of STAT3 expression increases the anti-tumor activity of T cells, NK cells, and neutrophils and enhances the maturation of DCs [95]. While increased phosphorylated-STAT3 (pSTAT3) expression has been shown to strongly correlate with increased T-cell infiltration in gliomas, this does not reflect an increase in immune response from these cells; on the contrary, the increase in pSTAT3 expression acts to suppress these immune cells. Although pSTAT3 does not show any independent correlation with Treg generation or prognosis implications in GBM patient survivability, pSTAT3 expression does have negative prognostic implications on survival in anaplastic astrocytoma patients [96]. STAT3 is phosphorylated by Janus kinase 2 (JAK2) [97], which is activated by cytokines and growth factors such as IL-6 [98] and epidermal growth factor (EGF) [97,98]. pSTAT3, which is

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Fig. 2. Induction of Treg and immunosuppression of glioma microenvironment. Malignant glioma cells release cytokines and factors that induce Tregs while directly initiating immunosuppression through T-cell apoptosis. The glioma cells also attract and stimulate dendritic cells, MDSC, and TAM to secrete immunosuppressive factors that also induce Tregs and T-cell apoptosis. The induction of Tregs, via proliferation as well as transient conversion of naïve T-cells, induces further increase in Tregs while ultimately creating an immunosuppressed microenvironment by suppressing the functions of natural killer cells, dendritic cells, and other lymphocytes as well as causing T-cell apoptosis.

overexpressed in gliomas [96], induces the expression of tumor-mediated immunosuppressive factors such as IL-10 [99], prostaglangin E2 (PGE2 ) [100], and TGF-␤ [101], all of which are mediators of Treg induction and function [102]. These STAT3mediated immunosuppressive factors also activate STAT3 in immune cells [103], such as macrophages, monocytes [104,105], DCs [93], T-cells [106], and Tregs [107]. This promotion of STAT3 activation by STAT3-induced secretions work as a positive feedback mechanism within the tumor microenvironment [97] (Fig. 2). Activation of STAT3 by hypoxia also results in the secretion of hypoxia induced factor-1␣ (HIF-1␣), which can induce Tregs [91]. HIF-1␣ can also promote expansion of CD133+ GBM Cancer-like Stem Cells (gCSCs) [108], which also propagates Tregs, hypoxia induction, and immunosuppression [89]. Hypoxia and STAT3 induce the release of various downstream immunosuppressive cytokines that disrupt normal immune responses in order to promote a tumorigenic microenvironment; these cytokines include vascular endothelial growth factor (VEGF) [109], transforming growth factor-␤ (TGF-␤) [110,111], Tcell immunoglobulin- and mucin domain-containing molecule-4 (TIM4) [70,112], and HIF-1␣ [113]. These regulating factors promote angiogenesis, while perturbing the normal immune response through apoptosis of effector T-cells and Treg induction. Hypoxia and STAT3 also induce the release of cytokines that promote the invasion and growth of glioma. Studies have shown strong correlation between tumor development and levels of soluble colony stimulating factor-1 (sCSF-1) [114], chemokine (C–C motif) ligand2 (CCL2) [115], and galectin-3 [116]. These cytokines enhance

glioma development through the promotion of tumor invasion, migration, and growth. 7. Conclusion Regulatory T-cells may contribute critically to the evasion of immunosurveillance by malignant gliomas – of which many mechanisms have been studied (Table 1) [88,89,95,117]. It is proposed that gliomas induce secretion of immunosuppressive factors such as HIF-␣ and PGE2 , which are responsible for Treg recruitment and preferential proliferation and survival within the tumor microenvironment. Increased percentages of Tregs in glioma patients may induce immunosuppressive factors such as IL-10, TGF-␤, and various other cytokines. This barrage of immune-compromising factors promotes tumor invasion, migration, and growth, leading to a poor prognosis in high-grade glioma patients. Thus, the ability to decrease Treg function by affecting its development and accumulation has promise in glioma treatment. Studies on the mechanisms of chemoattractants, such as CCL2, for the recruitment of the predominately thymus-derived Tregs across the blood–brain barrier to the tumor microenvironment can have clinical significance [118]. The use of monoclonal antibodies such as PC61 anti-CD25 or anti-IL-2␣ to inhibit Treg infiltration also has potential, but there have been in vivo studies that report an ineffective elimination in the intratumoral Treg population [119,120]. The recent approaches to inhibit indoleamine 2,3-dioxygenase (IDO), an enzyme crucial for immunosuppressive lymphocyte development and regulation of Treg levels, can avoid these limitations [88,121].

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Table 1 Mechanisms of immunosuppression and immune evasion by gliomas. Mechanism

Effect

Overexpression of COX-2 PGE2 production

Stimulate PGE2 synthesis. Induce IL-10 secretion. Suppress DC maturation. Suppress lymphocyte proliferation. Shift adaptive immunity to humoral responses. Act as a pro-angiogenic factor. Stimulate downstream immunosuppressive cytokine secretion. Stimulate proliferation of Tregs. Suppress DC maturation. Inhibits CD4+ T-cell activation.

TGF-B production IL-6 secretion CSF-1 secretion VEGF secretion STAT3 activation

Decreased expression of B7 costimulatory molecules B7-H1 expression IL-10 secretion by infiltrating monocytes and microglia Increase levels of MDSC in blood

Loss of HLA/MHC expression in lesions Tumor expression of Fas and FasL IDO induction

Induce apoptosis in activated T-cells. Stimulate proliferation of Tregs. Induce expression of Fas-Ligand. Induce apoptosis of activated T-cells. Induce apoptosis of activated T-cells. Alter T-cell recognition. Stimulate Treg proliferation in naïve T-cells. Evade lysis by cytotoxic CD8+ T-cells. Prevent tumor cell-induced apoptosis. Induces T-cell apoptosis. Stimulate Treg infiltration.

Glioblastoma multiforme is known to be unresponsive to treatment which is attributed to the immunosuppressed microenvironment that is induced by the tumor cells. The immunosuppressive functions and mechanisms of GBM have been under investigation – still many mechanisms require further elucidation. Understanding of the processes in which GBM exerts immunosuppression will allow for more effectively targeted therapies against it. This is not an exhaustive list.

IDO is highly expressed in glioma cells and elucidation of its mechanisms of Treg modulation can reveal potential immunotherapeutic treatments. Further research on the mechanisms and pathways by which regulatory T-cells facilitate the immunosuppressive GBM microenvironment may contribute to better optimization of immunotherapies against malignant gliomas. Acknowledgements Isaac Yang (senior author) was partially supported by a Visionary Fund Grant, an Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research UCLA Scholars in Translational Medicine Program Award, the Stein Oppenheimer Endowment Award, and the STOP CANCER Jason Dessel Memorial Seed Grant. References [1] Fathallah-Shaykh HM, McIntire DD. Brain tumors in the elderly: undefeated and gaining ground. Arch Neurol 1998;55:905–6. [2] El Andaloussi A, Lesniak MS. CD4+ CD25+ FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas. J Neurooncol 2007;83:145–52. [3] Carpentier AF, Meng Y. Recent advances in immunotherapy for human glioma. Curr Opin Oncol 2006;18:631–6. [4] El Andaloussi A, Han Y, Lesniak MS. Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors. J Neurosurg 2006;105:430–7. [5] Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC, et al. Human CD25+CD4+ T suppressor cell clones produce transforming growth factor beta, but not interleukin 10, and are distinct from type 1 T regulatory cells. J Exp Med 2002;196:1335–46. [6] Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001;2:816–22. [7] Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001;182:18–32.

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The role of regulatory T-cells in glioma immunology.

Despite recent advances in treatment, the prognosis for glioblastoma multiforme (GBM) remains poor. The lack of response to treatment in GBM patients ...
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