- Email: [email protected]
Immunology of brain tumors
Handbook of Clinical Neurology, Vol. 104 (3rd series) Neuro-oncology W. Grisold and R. Soffietti, Editors # 2012 Elsevier B.V. All rights reserved
Chapter 4
Immunology of brain tumors ¨ NTER EISELE, AND MICHAEL WELLER* PATRICK ROTH, GU Department of Neurology, University Hospital Zurich, Zurich, Switzerland
INTRODUCTION Despite recent advances in the treatment of brain tumors, they remain a dominant challenge in the field of neurology. The prognosis, notably of malignant gliomas, is dismal for several reasons. In addition to their infiltrating growth pattern and resistance to different apoptotic stimuli, gliomas are characterized by an immunosuppressive phenotype (Parney et al., 2000b; Gomez and Kruse, 2006). Glioblastoma, the most malignant form of all brain tumors, is paradigmatic for tumor-associated immunosuppression, but low-grade gliomas and other tumor entities, such as medulloblastomas and ependymomas, also display immunosuppressive features. This chapter deals with the interaction of brain tumors with cells of the immune system, a possible target for future therapeutic strategies.
GENERAL PRINCIPLES OF IMMUNOLOGY The immune system comprises different types of cell that allow for protection against pathogens. In principle, the network of immune cells is also able to attack and destroy cells that have undergone malignant transformation. Due to its complexity, the following is only a very brief synopsis. The effector cells of the immune system are T and B lymphocytes, and natural killer (NK) cells. The latter can attack cells without mediation by other immune cells and are inhibited by the expression of major histocompatibility complex (MHC) molecules on their targets (Lanier, 2005). NK cells, together with granulocytes and macrophages, are part of the innate immune system. These cells can respond quickly to pathogens and tumor cells; however, their effects are limited and they are not able to build up an ‘immunological memory’. The adaptive immune system includes B and T cells, which are characterized by a specificity to
antigens presented to them by cell surface-bound MHC molecules. T lymphocytes comprise several subgroups including T-helper cells, cytotoxic T lymphocytes (CTLs), and regulatory T cells (Treg). T-helper cells provide assistance to other cells of the immune system in mounting immune responses, by causing cell activation or by the secretion of signaling molecules. After activation and proliferation, CTLs can attack their target cells either by a mechanism involving the expression of death ligands such as CD95 (Fas/Apo-1) ligand on their surface or in a perforin-dependent manner (Russell and Ley, 2002). Treg are immunosuppressive and are involved in maintaining immune tolerance. Recent studies in patients with glioma and animal models have pointed to a prominent role for Treg in impairing a sufficient immune response against gliomas (Fecci et al., 2006; Grauer et al., 2007). B cells, which are presumably less important in generating immune responses against malignant cells, attack tumor cells by secretion of antigen-specific antibodies. A common feature of B and T lymphocytes is their ability to become memory cells that can persist for years or even decades. When the same antigen is presented again, these memory cells can build up a new and very potent immune response within very short time. To become activated, B and T cells require costimulatory signals by ‘professional’ antigen-presenting cells (APCs). Cells that display features of APCs include monocytes, macrophages, and dendritic cells (DCs). APCs encountering antigens are able to present them on their cell surface by MHC class II molecules with additional costimulatory signals, such as CD80 or CD86. In addition to cellular components of the immune system there exists an extremely complex network of cytokines. These soluble signaling molecules, such as interleukin (IL)-2 and interferon (IFN)-g, are essential for interactions between immune cells and their targets.
*Correspondence to: Michael Weller, MD, University Hospital Zurich, Department of Neurology, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. Tel: þ41 (0)44 255 5511; Fax: þ 41 (0)44 255 4380; E-mail: [email protected]
46
P. ROTH ET AL.
IMMUNOLOGY IN THE CENTRAL NERVOUS SYSTEM Immune surveillance in the central nervous system (CNS) is somewhat different to that in other parts of the body. The existence of the blood–brain barrier, formed by endothelial cells, smooth muscle cells, and astrocytes, hampers the migration of lymphocytes from the blood into the CNS (Doolittle et al., 2005). Plasma proteins, such as complement components, are also prevented from passing readily into the brain. Although microglial cells are thought to be the APCs of the brain, it has remained unclear whether they have the same potency to present antigens to other cells of the immune system compared with extracerebral APCs (Streit et al., 2005). Finally, except for microglia, the expression of MHC molecules on brain parenchymal cells such as neurons and glial cells is low, complicating the optimal presentation of antigens (Sikorski and Lesniak, 2005). Due to these facts, the CNS has been called an ‘immunoprivileged site’ for a long time. However, there is evidence that powerful immune responses occur in the CNS, so it should perhaps rather be considered an ‘immunologically specialized site’. This can be seen in other pathological conditions, such as inflammatory diseases with an undisputed presence of immunological reactions in the CNS. In many brain tumors, the blood–brain barrier is not intact, thereby allowing the penetration of increased numbers of lymphocytes into the CNS (Hickey et al., 1991). Further, the role of microglia and their antigen-presenting capacities has partly been clarified. Microglial cells are of hematopoietic origin and they express MHC class I and II molecules, as well as certain costimulatory molecules. Their ability to present antigens has been demonstrated in several in vitro and in vivo studies. Furthermore, there is evidence that T lymphocytes patrolling the brain can be stimulated in cervical lymph nodes. However, due to the lack of a classical lymphatic drainage in the brain, the connection between immune cells in the brain and the lymphatic tissues in the periphery is still not fully understood (Karman et al., 2004).
INTERACTIONS OF TUMOR CELLS WITH IMMUNE CELLS Brain tumors of different cellular origin are able to interact with cells of the immune system in different ways. The most frequent intrinsic brain tumors are gliomas, and their immunological phenotype has been examined in most depth. Metastasic disease outside the brain is very rare with these tumors but there are reports of extraneural metastases following organ transplantation. Apparently, in these immunosuppressed patients, tumor growth was no longer controlled outside the CNS,
a sometimes reversible condition after reduction of immunosuppressive therapy (Schweitzer et al., 2001). Overall, these findings suggest that there is control of tumor growth outside the brain, whereas intracerebral growth may not be affected owing to a local immunosuppression. Glioma cells, in particular, express activatory ligands, a prerequisite for effective T- and NK-cell responses (Friese et al., 2003). The expression of MHC class I molecules by glioma cells has been shown in vitro (Parney et al., 2000a). The situation in vivo is less clear, but the expression and possible induction of MCH class I molecules seems likely (Saito et al., 1988). However, the rather low expression of MHC class I molecules on malignant glioma cells limits the presentation of antigens and prevents potent T-cell responses. More recent studies have shown that glioma cells display deficits in their antigen-processing machinery, thereby precluding effective recognition and lysis by T lymphocytes (Facoetti et al., 2005). On the other hand, NK cells, as part of the innate immune system, are inhibited by the presence of MHC molecules. Therefore, it may be assumed that a level of MHC expression exists that is too low for effective antigen presentation but is high enough to prevent tumor cell lysis by NK cells.
THE CONTROVERSIAL ROLE OF MICROGLIAL CELLS Microglial cells and macrophages have been identified as the predominant immune cells infiltrating human gliomas (Hussain et al., 2006). A similar observation was made in rodent glioma models (Badie and Schartner, 2001). Nevertheless, the biological role of microglia and macrophages in human gliomas remains ambiguous. Whether the accumulation of microglia and macrophages is an attempt of innate immunity to combat the tumor, or whether these cells promote further immunosuppression and glioma invasion, is still unclear, with emerging emphasis on the latter (Watters et al., 2005). Several glioma-derived factors, such as monocyte chemoattractant protein-1, attract microglial cells to gliomas and promote their aggressive growth pattern in a rat glioma model (Platten et al., 2003). Furthermore, a considerable number of publications have investigated the potential of microglia to promote glioma proliferation, migration, and angiogenesis (Watters et al., 2005). A possible immunological antitumorigenic role is the presentation of tumor antigens to infiltrating lymphocytes and the secretion of proinflammatory cytokines. However, the capacity of glioma-infiltrating microglia/macrophages to present tumor antigens remains under discussion as their expression of costimulatory molecules, such as CD80, CD86, and CD40, and the upregulation of MHC
IMMUNOLOGY OF class II molecules may be insufficient (Schartner et al., 2005; Hussain et al., 2006). Overall, further studies are urgently needed to clarify the immunological role of microglial cells in gliomas and their possible function as target for immunotherapeutic strategies.
TUMOR-DERIVED IMMUNOSUPPRESSION Transforming growth factor-b Glioma cells express and release various factors that inhibit cells of the immune system. The most prominent immunosuppressive factor secreted by glioblastomas is the cytokine transforming growth factor (TGF)-b. Beside its multiple capacities of modulating innate and adaptive immune functions, TGF-b also promotes the migration and invasion of glioma cells in surrounding healthy brain tissue, and is involved in angiogenesis (Jensen, 1998; Wick et al., 2006). Among various immunosuppressive factors secreted by gliomas, TGF-b takes a central role. TGF-b is present in its active form in glioma cyst fluids and in the cerebrospinal fluid of patients with glioma. Numerous studies have demonstrated a strong association of raised TGF-b levels with increasing grade of malignancy of gliomas. Three isoforms, TGF-b1, -b2, and -b3, are found in mammals (Govinden and Bhoola, 2003). TGF-b is kept in an inactive form during its synthesis and secretion. The 55-kDa precursor form of TGF-b is processed by proteases of the furin family (Leitlein et al., 2001). A dimer of the liberated 12.5-kDa fragment forms active TGF-b. Associated with the larger fragment, the latency-associated peptide (LAP), it is kept inactive in the small latent TGF-b complex. Together with members of the latent TGF-b-binding proteins family, this complex forms the large latent TGF-b complex (Oklu and Hesketh, 2000). To be activated, TGF-b has to be released from the latent complex. Active TGF-b exerts its functions via binding to the TGF-b receptors (TbR). Three receptors have been described: the transmembrane receptors TbR types I and II with a serine/threonine kinase activity, and the membrane-bound TbR type III which lacks intrinsic kinase activity. TGF-b1 and -b3 bind with high affinity to TbRII, whereas for effective binding of TGF-b2 the TbRIII is essential. Upon activation of the TGF-b–receptor complex after ligand binding, the TGF-b signal is forwarded through the SMA- and MAD-related protein (SMAD) family of transcriptional regulators. SMAD proteins are, in concert with other transcription factors, coactivators and corepressors involved in the regulation of a wide variety of genes (Shi and Massague, 2003). TGF-b is involved in the proliferation, differentiation, and survival of T cells and acts as a functional
BRAIN TUMORS
47
antagonist of IL-2, a central cytokine for T-cell activity. TGF-b negatively regulates the differentiation of naive T cells to type 1 T-helper lymphocytes, and thus interferes with effective cellular immunity (Gorelik and Flavell, 2001). Furthermore, it inhibits the production of the important effector cytokine IFN-g in differentiated T-helper cells and, even more importantly, also negatively regulates the differentiation and proliferation of CTLs (Ludviksson et al., 2000). Furthermore TGF-b disarms CTLs by downregulating their effector molecules, perforin and CD95 ligand (Genestier et al., 1999; Ahmadzadeh and Rosenberg, 2005). The question of whether TGF-b might be able to generate tumorassociated Treg, which block potent immune responses, is still under discussion (Chen et al., 2003). The activation and cytolytic function of NK cells as another subset of lymphocytes are also affected by TGF-b. The activation of NK cells depends on a balance of signals mediated by inhibiting and activating receptors (Lanier, 2003). The most prominent activating NK-cell receptor investigated in the context of glioma is NKG2D, which can also provide costimulatory signals to CTLs. Triggering of NKG2D initiates a perforin-mediated cytolytic response against tumorigenic cells (Hayakawa et al., 2002). NKG2D interacts with different MHC class I homologous ligands (NKG2DL). In humans, these are MHC class I chain-related molecules A (MICA) and MICB, UL16-binding proteins (ULBP) 1–3, ULBP4/RAET1E and RAET1G (Cosman et al., 2001; Chalupny et al., 2003; Bacon et al., 2004). In pathological conditions such as brain tumors, NKG2DL expression is upregulated (Bauer et al., 1999; Das et al., 2001; Friese et al., 2003). NKG2DL are expressed in human gliomas in vivo and thus may label tumor cells for recognition by NKG2D-expressing immune effector cells. However, MICA and ULBP2 expression levels are downregulated towards baseline levels in glioblastomas (Eisele et al., 2006). In vitro TGF-b downregulates MICA and ULBP2 on glioma cells and also the NKG2D receptor on NK cells (Friese et al., 2004). Other activating NK-cell receptors such as NKp30, NKp40, and NKp46 are also partially downregulated by TGF-b (Castriconi et al., 2003). TGF-b inhibits the maturation of DCs and thereby promotes the formation of an immature phenotype of these cells (Yamaguchi et al., 1997). MHC class II molecules on DCs are downregulated by TGF-b, impairing their capacity for antigen presentation (Geissmann et al., 1999). Because of its various modes of action, TGF-b seems to be an attractive target for immunotherapeutic strategies. Several approaches, using TGF-b inhibitors and antisense strategies, have been used in glioma mouse models and have shown promising results (Jachimczak et al., 1993; Friese et al., 2004; Uhl et al., 2004).
48
P. ROTH ET AL.
Nonclassical major histocompatibility complex class I molecules As mentioned above, glioma cells show an intermediate expression level of classical MHC class I molecules that inhibit NK cell-mediated lysis by interacting with inhibitory killer immunoglobulin-like receptors (KIR). In contrast to these classical MHC molecules, the nonclassical MHC class I molecules (class Ib), human leukocyte antigen (HLA)-E and HLA-G, show an expression pattern that is limited to few tissues, such as placenta. However, in vitro and in vivo studies have confirmed their surface expression by glioma cells. HLA-E can hamper the killing efficacy of NK cells by interacting with its main receptor, CD94/NKG2A (Wischhusen et al., 2005). The inhibitory NKG2A receptor is also found on T cells, and its expression is upregulated by TGF-b (Bertone et al., 1999). HLA-G shows limited polymorphism and its alternatively spliced mRNA encodes at least seven different isoforms, including membrane-bound and soluble proteins. HLA-G acts as a ligand for several inhibitory immune cell receptors and inhibits, in particular, T-cell responses (Wiendl et al., 2002).
Further immunosuppressive factors During the past decade, numerous molecules have been identified as potential mediators of glioma-associated immunosuppression. One of the first was IL-10, a cytokine with immune modulatory properties that is released by malignant glioma cells. In vitro studies suggested that IL-10 interferes with immune cell-derived IFN-g and TNF-a, and downregulates MHC class II molecules (Hishii et al., 1995). It remains elusive whether these effects are important for the in vivo situation of glioma immunology. In addition, more than 10 years ago prostaglandin (PG) E2 was identified as a further glioma-derived molecule with immunosuppressive effects, and might shift T-cell development to a regulatory subtype (Lauro et al., 1986; Akasaki et al., 2004). T and NK cells can attack tumor cells by the expression of CD95 ligand. Reduced expression of its receptor CD95 on glioma cells and expression of the soluble decoy receptor 3 (DcR3), which lacks a transmembrane domain, result in a disruption of the CD95 ligand-dependent tumor cell attack. On the other hand, CD95 ligand is also expressed by malignant glioma cells. It can thereby induce apoptosis on CD95expressing cells of the immune system (Saas et al., 1997). Novel molecules that may contribute to the immunosuppressive phenotype of malignant glioma cells include B7 homolog 1 (B7-H1), regeneration and tolerance factor (RTF), and lectin-like transcript 1 (LLT1). The interaction of glioma-derived B7-H1 with
its receptor PD-1 inhibits T-cell responses (Wintterle et al., 2003). Interestingly, loss of the tumor suppressor phosphatase and tensin homolog (PTEN) leads to immunoresistance that is mediated by B7-H1 (Parsa et al., 2007). RTF exists as a transmembrane and a soluble protein that interacts with a so far unknown eceptor. It is massively overexpressed in malignant glioma cells compared with expression in normal human brain tissue. RTF expression by malignant glioma cells leads to impaired T- and NK-cell cytotoxicity (Roth et al., 2006). LLT1 is a novel ligand for the inhibitory NK-cell receptor CD161. Expression of LLT1 by glioma cells suppresses the killing efficiency of NK cells in vitro (Roth et al., 2007). CD70 is a tumor necrosis factor-related cell-surface ligand, and its receptor, CD27, is expressed on different immune cell populations. The role of CD70 in the immunobiology of malignant gliomas is rather controversial. CD70, expressed on the cell surface of glioma cells, induces B- and T-cell apoptosis in vitro (Wischhusen et al., 2002). However, in vivo studies using a syngeneic murine glioma model have suggested that the net effect of CD70 expression in gliomas is immunostimulatory rather than paralytic (Aulwurm et al., 2006). The role of the immune system in other tumor entities of the CNS, such as meningioma, ependymoma, and medulloblastoma, remains less clear. There are a few reports indicating a possible immunomodulatory function for these tumors (Kempuraj et al., 2004; Kumar et al., 2006). The same applies to brain metastases from other tumor entities. A few reports have suggested local immunosuppression in the brain by metastatic disease, but it has to be considered that patients with systemic tumors suffer from a general impairment of their immune system (Ohshima et al., 2003; Whiteside, 2006). Overall, the importance of these observations for prognosis and clinical practice, and for the development of immunotherapeutic strategies for the treatment of these tumors, has not yet been investigated sufficiently.
SUMMARYAND CONCLUSIONS Brain tumors of different origin, but notably malignant gliomas, are characterized by their immunosuppressive properties which allow them to escape the host’s immune surveillance. The activating immune cell ligands that are expressed by tumor cells, together with potentially immunogenic antigens, are overridden by numerous immune inhibitory signals, with TGF-b as the master immunosuppressive molecule (Figure 4.1). The ongoing investigation of mechanisms of tumorderived immunosuppression allows for an increasing understanding of brain tumor immunology. Targeting
IMMUNOLOGY OF BRAIN TUMORS MHC class I NKG2DL CD95 ligand
Glioma cells
TGF-b IL-10 PGE2 HLA-E HLA-G B7-H1 RTF
NK cells
NKG2D CD94/NKG2A Proliferation Cytotoxicity
IFN-g IL-2 NKG2D Proliferation T cells Cytotoxicity MHC class II CD80, CD86 Microglia
Antigen presentation
Fig. 4.1. Mediators of glioma-associated immunosuppression: immune inhibitory signals expressed by malignant glioma cells (black); autocrine effects (blue); and influence on different subpopulations of lymphocytes and microglial cells (red). For abbreviations and details see main text. (Adapted from Fenstermaker and Ciesielski (2004).)
different mechanisms of tumor-derived immunosuppression, such as inhibition of TGF-b, may represent a promising strategy for future immunotherapeutic approaches.
REFERENCES Ahmadzadeh M, Rosenberg SA (2005). TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol 174: 5215–5223. Akasaki Y, Liu G, Chung NH et al. (2004). Induction of a CD4þ T regulatory type 1 response by cyclooxygenase2-overexpressing glioma. J Immunol 173: 4352–4359. Aulwurm S, Wischhusen J, Friese M et al. (2006). Immune stimulatory effects of CD70 override CD70-mediated immune cell apoptosis in rodent glioma models and confer long-lasting antiglioma immunity in vivo. Int J Cancer 118: 1728–1735. Bacon L, Eagle RA, Meyer M et al. (2004). Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D. J Immunol 173: 1078–1084. Badie B, Schartner J (2001). Role of microglia in glioma biology. Microsc Res Tech 54: 106–113. Bauer S, Groh V, Wu J et al. (1999). Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285: 727–729. Bertone S, Schiavetti F, Bellomo R et al. (1999). Transforming growth factor-beta-induced expression of CD94/ NKG2A inhibitory receptors in human T lymphocytes. Eur J Immunol 29: 23–29. Castriconi R, Cantoni C, Della Chiesa M et al. (2003). Transforming growth factor beta 1 inhibits expression of nkp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 100: 4120–4125.
49
Chalupny NJ, Sutherland CL, Lawrence WA et al. (2003). ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun 305: 129–135. Chen W, Jin W, Hardegen N et al. (2003). Conversion of peripheral CD4þCD25 naive T cells to CD4þCD25þ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198: 1875–1886. Cosman D, Mullberg J, Sutherland CL et al. (2001). Ulbps, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14: 123–133. Das H, Groh V, Kuijl C et al. (2001). MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigendependent effector function. Immunity 15: 83–93. Doolittle ND, Abrey LE, Bleyer WA et al. (2005). New frontiers in translational research in neuro-oncology and the blood–brain barrier: report of the tenth annual Blood–Brain Barrier Disruption Consortium Meeting. Clin Cancer Res 11: 421–428. Eisele G, Wischhusen J, Mittelbronn M et al. (2006). TGFbeta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 129: 2416–2425. Facoetti A, Nano R, Zelini P et al. (2005). Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors. Clin Cancer Res 11: 8304–8311. Fecci PE, Mitchell DA, Whitesides JF et al. (2006). Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66: 3294–3302. Fenstermaker RA, Ciesielski MJ (2004). Immunotherapeutic strategies for malignant glioma. Cancer Control 11: 181–191. Friese MA, Platten M, Lutz SZ et al. (2003). MICA/NKG2Dmediated immunogene therapy of experimental gliomas. Cancer Res 63: 8996–9006. Friese MA, Wischhusen J, Wick W et al. (2004). RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res 64: 7596–7603. Geissmann F, Revy P, Regnault A et al. (1999). TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 162: 4567–4575. Genestier L, Kasibhatla S, Brunner T et al. (1999). Transforming growth factor beta1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc. J Exp Med 189: 231–239. Gomez GG, Kruse CA (2006). Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene Ther Mol Biol 10: 133–146. Gorelik L, Flavell RA (2001). Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7: 1118–1122. Govinden R, Bhoola KD (2003). Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther 98: 257–265. Grauer OM, Nierkens S, Bennink E et al. (2007). CD4þfoxp3þ regulatory T cells gradually accumulate in
50
P. ROTH ET AL.
gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int J Cancer 121: 95–105. Hayakawa Y, Kelly JM, Westwood JA et al. (2002). Cutting edge: tumor rejection mediated by NKG2D receptor– ligand interaction is dependent upon perforin. J Immunol 169: 5377–5381. Hickey WF, Hsu BL, Kimura H (1991). T-lymphocyte entry into the central nervous system. J Neurosci Res 28: 254–260. Hishii M, Nitta T, Ishida H et al. (1995). Human gliomaderived interleukin-10 inhibits antitumor immune responses in vitro. Neurosurgery 37: 1160–1166. Hussain SF, Yang D, Suki D et al. (2006). The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro-oncol 8: 261–279. Jachimczak P, Bogdahn U, Schneider J et al. (1993). The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. J Neurosurg 78: 944–951. Jensen RL (1998). Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review. Surg Neurol 49: 189–195. Karman J, Ling C, Sandor M et al. (2004). Dendritic cells in the initiation of immune responses against central nervous system-derived antigens. Immunol Lett 92: 107–115. Kempuraj D, Devi RS, Madhappan B et al. (2004). T lymphocyte subsets and immunoglobulins in intracranial tumor patients before and after treatment, and based on histological type of tumors. Int J Immunopathol Pharmacol 17: 57–64. Kumar R, Kamdar D, Madden L et al. (2006). Th1/Th2 cytokine imbalance in meningioma, anaplastic astrocytoma and glioblastoma multiforme patients. Oncol Rep 15: 1513–1516. Lanier LL (2003). Natural killer cell receptor signaling. Curr Opin Immunol 15: 308–314. Lanier LL (2005). NK cell recognition. Annu Rev Immunol 23: 225–274. Lauro GM, Di Lorenzo N, Grossi M et al. (1986). Prostaglandin E2 as an immunomodulating factor released in vitro by human glioma cells. Acta Neuropathol (Berl) 69: 278–282. Leitlein J, Aulwurm S, Waltereit R et al. (2001). Processing of immunosuppressive pro-TGF-beta 1,2 by human glioblastoma cells involves cytoplasmic and secreted furinlike proteases. J Immunol 166: 7238–7243. Ludviksson BR, Seegers D, Resnick AS et al. (2000). The effect of TGF-beta1 on immune responses of naive versus memory CD4þ Th1/Th2 T cells. Eur J Immunol 30: 2101–2111. Ohshima K, Hamasaki M, Makimoto Y et al. (2003). Differential chemokine, chemokine receptor, cytokine and cytokine receptor expression in pulmonary adenocarcinoma: diffuse down-regulation is associated with immune evasion and brain metastasis. Int J Oncol 23: 965–973. Oklu R, Hesketh R (2000). The latent transforming growth factor beta binding protein (LTBP) family. Biochem J 352: 601–610.
Parney IF, Farr-Jones MA, Chang LJ et al. (2000a). Human glioma immunobiology in vitro: implications for immunogene therapy. Neurosurgery 46: 1169–1177. Parney IF, Hao C, Petruk KC (2000b). Glioma immunology and immunotherapy. Neurosurgery 46: 778–791. Parsa AT, Waldron JS, Panner A et al. (2007). Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13: 84–88. Platten M, Kretz A, Naumann U et al. (2003). Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann Neurol 54: 388–392. Roth P, Aulwurm S, Gekel I et al. (2006). Regeneration and tolerance factor: a novel mediator of glioblastoma-associated immunosuppression. Cancer Res 66: 3852–3858. Roth P, Mittelbronn M, Wick W et al. (2007). Malignant glioma cells counteract antitumor immune responses through expression of lectin-like transcript-1. Cancer Res 67: 3540–3544. Russell JH, Ley TJ (2002). Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 20: 323–370. Saas P, Walker PR, Hahne M et al. (1997). Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? J Clin Invest 99: 1173–1178. Saito T, Tanaka R, Yoshida S et al. (1988). Immunohistochemical analysis of tumor-infiltrating lymphocytes and major histocompatibility antigens in human gliomas and metastatic brain tumors. Surg Neurol 29: 435–442. Schartner JM, Hagar AR, Van Handel M et al. (2005). Impaired capacity for upregulation of MHC class II in tumor-associated microglia. Glia 51: 279–285. Schweitzer T, Vince GH, Herbold C et al. (2001). Extraneural metastases of primary brain tumors. J Neurooncol 53: 107–114. Shi Y, Massague J (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113: 685–700. Sikorski CW, Lesniak MS (2005). Immunotherapy for malignant glioma: current approaches and future directions. Neurol Res 27: 703–716. Streit WJ, Conde JR, Fendrick SE et al. (2005). Role of microglia in the central nervous system’s immune response. Neurol Res 27: 685–691. Uhl M, Aulwurm S, Wischhusen J et al. (2004). SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 64: 7954–7961. Watters JJ, Schartner JM, Badie B (2005). Microglia function in brain tumors. J Neurosci Res 81: 447–455. Whiteside TL (2006). Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol 16: 3–15. Wick W, Naumann U, Weller M (2006). Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. Curr Pharm Des 12: 341–349. Wiendl H, Mitsdoerffer M, Hofmeister V et al. (2002). A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 168: 4772–4780.
IMMUNOLOGY OF BRAIN TUMORS Wintterle S, Schreiner B, Mitsdoerffer M et al. (2003). Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res 63: 7462–7467. Wischhusen J, Jung G, Radovanovic I et al. (2002). Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. Cancer Res 62: 2592–2599.
51
Wischhusen J, Friese MA, Mittelbronn M et al. (2005). HLAE protects glioma cells from NKG2D-mediated immune responses in vitro: implications for immune escape in vivo. J Neuropathol Exp Neurol 64: 523–528. Yamaguchi Y, Tsumura H, Miwa M et al. (1997). Contrasting effects of TGF-beta 1 and TNF-alpha on the development of dendritic cells from progenitors in mouse bone marrow. Stem Cells 15: 144–153.
Chapter 4
Immunology of brain tumors ¨ NTER EISELE, AND MICHAEL WELLER* PATRICK ROTH, GU Department of Neurology, University Hospital Zurich, Zurich, Switzerland
INTRODUCTION Despite recent advances in the treatment of brain tumors, they remain a dominant challenge in the field of neurology. The prognosis, notably of malignant gliomas, is dismal for several reasons. In addition to their infiltrating growth pattern and resistance to different apoptotic stimuli, gliomas are characterized by an immunosuppressive phenotype (Parney et al., 2000b; Gomez and Kruse, 2006). Glioblastoma, the most malignant form of all brain tumors, is paradigmatic for tumor-associated immunosuppression, but low-grade gliomas and other tumor entities, such as medulloblastomas and ependymomas, also display immunosuppressive features. This chapter deals with the interaction of brain tumors with cells of the immune system, a possible target for future therapeutic strategies.
GENERAL PRINCIPLES OF IMMUNOLOGY The immune system comprises different types of cell that allow for protection against pathogens. In principle, the network of immune cells is also able to attack and destroy cells that have undergone malignant transformation. Due to its complexity, the following is only a very brief synopsis. The effector cells of the immune system are T and B lymphocytes, and natural killer (NK) cells. The latter can attack cells without mediation by other immune cells and are inhibited by the expression of major histocompatibility complex (MHC) molecules on their targets (Lanier, 2005). NK cells, together with granulocytes and macrophages, are part of the innate immune system. These cells can respond quickly to pathogens and tumor cells; however, their effects are limited and they are not able to build up an ‘immunological memory’. The adaptive immune system includes B and T cells, which are characterized by a specificity to
antigens presented to them by cell surface-bound MHC molecules. T lymphocytes comprise several subgroups including T-helper cells, cytotoxic T lymphocytes (CTLs), and regulatory T cells (Treg). T-helper cells provide assistance to other cells of the immune system in mounting immune responses, by causing cell activation or by the secretion of signaling molecules. After activation and proliferation, CTLs can attack their target cells either by a mechanism involving the expression of death ligands such as CD95 (Fas/Apo-1) ligand on their surface or in a perforin-dependent manner (Russell and Ley, 2002). Treg are immunosuppressive and are involved in maintaining immune tolerance. Recent studies in patients with glioma and animal models have pointed to a prominent role for Treg in impairing a sufficient immune response against gliomas (Fecci et al., 2006; Grauer et al., 2007). B cells, which are presumably less important in generating immune responses against malignant cells, attack tumor cells by secretion of antigen-specific antibodies. A common feature of B and T lymphocytes is their ability to become memory cells that can persist for years or even decades. When the same antigen is presented again, these memory cells can build up a new and very potent immune response within very short time. To become activated, B and T cells require costimulatory signals by ‘professional’ antigen-presenting cells (APCs). Cells that display features of APCs include monocytes, macrophages, and dendritic cells (DCs). APCs encountering antigens are able to present them on their cell surface by MHC class II molecules with additional costimulatory signals, such as CD80 or CD86. In addition to cellular components of the immune system there exists an extremely complex network of cytokines. These soluble signaling molecules, such as interleukin (IL)-2 and interferon (IFN)-g, are essential for interactions between immune cells and their targets.
*Correspondence to: Michael Weller, MD, University Hospital Zurich, Department of Neurology, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland. Tel: þ41 (0)44 255 5511; Fax: þ 41 (0)44 255 4380; E-mail: [email protected]
46
P. ROTH ET AL.
IMMUNOLOGY IN THE CENTRAL NERVOUS SYSTEM Immune surveillance in the central nervous system (CNS) is somewhat different to that in other parts of the body. The existence of the blood–brain barrier, formed by endothelial cells, smooth muscle cells, and astrocytes, hampers the migration of lymphocytes from the blood into the CNS (Doolittle et al., 2005). Plasma proteins, such as complement components, are also prevented from passing readily into the brain. Although microglial cells are thought to be the APCs of the brain, it has remained unclear whether they have the same potency to present antigens to other cells of the immune system compared with extracerebral APCs (Streit et al., 2005). Finally, except for microglia, the expression of MHC molecules on brain parenchymal cells such as neurons and glial cells is low, complicating the optimal presentation of antigens (Sikorski and Lesniak, 2005). Due to these facts, the CNS has been called an ‘immunoprivileged site’ for a long time. However, there is evidence that powerful immune responses occur in the CNS, so it should perhaps rather be considered an ‘immunologically specialized site’. This can be seen in other pathological conditions, such as inflammatory diseases with an undisputed presence of immunological reactions in the CNS. In many brain tumors, the blood–brain barrier is not intact, thereby allowing the penetration of increased numbers of lymphocytes into the CNS (Hickey et al., 1991). Further, the role of microglia and their antigen-presenting capacities has partly been clarified. Microglial cells are of hematopoietic origin and they express MHC class I and II molecules, as well as certain costimulatory molecules. Their ability to present antigens has been demonstrated in several in vitro and in vivo studies. Furthermore, there is evidence that T lymphocytes patrolling the brain can be stimulated in cervical lymph nodes. However, due to the lack of a classical lymphatic drainage in the brain, the connection between immune cells in the brain and the lymphatic tissues in the periphery is still not fully understood (Karman et al., 2004).
INTERACTIONS OF TUMOR CELLS WITH IMMUNE CELLS Brain tumors of different cellular origin are able to interact with cells of the immune system in different ways. The most frequent intrinsic brain tumors are gliomas, and their immunological phenotype has been examined in most depth. Metastasic disease outside the brain is very rare with these tumors but there are reports of extraneural metastases following organ transplantation. Apparently, in these immunosuppressed patients, tumor growth was no longer controlled outside the CNS,
a sometimes reversible condition after reduction of immunosuppressive therapy (Schweitzer et al., 2001). Overall, these findings suggest that there is control of tumor growth outside the brain, whereas intracerebral growth may not be affected owing to a local immunosuppression. Glioma cells, in particular, express activatory ligands, a prerequisite for effective T- and NK-cell responses (Friese et al., 2003). The expression of MHC class I molecules by glioma cells has been shown in vitro (Parney et al., 2000a). The situation in vivo is less clear, but the expression and possible induction of MCH class I molecules seems likely (Saito et al., 1988). However, the rather low expression of MHC class I molecules on malignant glioma cells limits the presentation of antigens and prevents potent T-cell responses. More recent studies have shown that glioma cells display deficits in their antigen-processing machinery, thereby precluding effective recognition and lysis by T lymphocytes (Facoetti et al., 2005). On the other hand, NK cells, as part of the innate immune system, are inhibited by the presence of MHC molecules. Therefore, it may be assumed that a level of MHC expression exists that is too low for effective antigen presentation but is high enough to prevent tumor cell lysis by NK cells.
THE CONTROVERSIAL ROLE OF MICROGLIAL CELLS Microglial cells and macrophages have been identified as the predominant immune cells infiltrating human gliomas (Hussain et al., 2006). A similar observation was made in rodent glioma models (Badie and Schartner, 2001). Nevertheless, the biological role of microglia and macrophages in human gliomas remains ambiguous. Whether the accumulation of microglia and macrophages is an attempt of innate immunity to combat the tumor, or whether these cells promote further immunosuppression and glioma invasion, is still unclear, with emerging emphasis on the latter (Watters et al., 2005). Several glioma-derived factors, such as monocyte chemoattractant protein-1, attract microglial cells to gliomas and promote their aggressive growth pattern in a rat glioma model (Platten et al., 2003). Furthermore, a considerable number of publications have investigated the potential of microglia to promote glioma proliferation, migration, and angiogenesis (Watters et al., 2005). A possible immunological antitumorigenic role is the presentation of tumor antigens to infiltrating lymphocytes and the secretion of proinflammatory cytokines. However, the capacity of glioma-infiltrating microglia/macrophages to present tumor antigens remains under discussion as their expression of costimulatory molecules, such as CD80, CD86, and CD40, and the upregulation of MHC
IMMUNOLOGY OF class II molecules may be insufficient (Schartner et al., 2005; Hussain et al., 2006). Overall, further studies are urgently needed to clarify the immunological role of microglial cells in gliomas and their possible function as target for immunotherapeutic strategies.
TUMOR-DERIVED IMMUNOSUPPRESSION Transforming growth factor-b Glioma cells express and release various factors that inhibit cells of the immune system. The most prominent immunosuppressive factor secreted by glioblastomas is the cytokine transforming growth factor (TGF)-b. Beside its multiple capacities of modulating innate and adaptive immune functions, TGF-b also promotes the migration and invasion of glioma cells in surrounding healthy brain tissue, and is involved in angiogenesis (Jensen, 1998; Wick et al., 2006). Among various immunosuppressive factors secreted by gliomas, TGF-b takes a central role. TGF-b is present in its active form in glioma cyst fluids and in the cerebrospinal fluid of patients with glioma. Numerous studies have demonstrated a strong association of raised TGF-b levels with increasing grade of malignancy of gliomas. Three isoforms, TGF-b1, -b2, and -b3, are found in mammals (Govinden and Bhoola, 2003). TGF-b is kept in an inactive form during its synthesis and secretion. The 55-kDa precursor form of TGF-b is processed by proteases of the furin family (Leitlein et al., 2001). A dimer of the liberated 12.5-kDa fragment forms active TGF-b. Associated with the larger fragment, the latency-associated peptide (LAP), it is kept inactive in the small latent TGF-b complex. Together with members of the latent TGF-b-binding proteins family, this complex forms the large latent TGF-b complex (Oklu and Hesketh, 2000). To be activated, TGF-b has to be released from the latent complex. Active TGF-b exerts its functions via binding to the TGF-b receptors (TbR). Three receptors have been described: the transmembrane receptors TbR types I and II with a serine/threonine kinase activity, and the membrane-bound TbR type III which lacks intrinsic kinase activity. TGF-b1 and -b3 bind with high affinity to TbRII, whereas for effective binding of TGF-b2 the TbRIII is essential. Upon activation of the TGF-b–receptor complex after ligand binding, the TGF-b signal is forwarded through the SMA- and MAD-related protein (SMAD) family of transcriptional regulators. SMAD proteins are, in concert with other transcription factors, coactivators and corepressors involved in the regulation of a wide variety of genes (Shi and Massague, 2003). TGF-b is involved in the proliferation, differentiation, and survival of T cells and acts as a functional
BRAIN TUMORS
47
antagonist of IL-2, a central cytokine for T-cell activity. TGF-b negatively regulates the differentiation of naive T cells to type 1 T-helper lymphocytes, and thus interferes with effective cellular immunity (Gorelik and Flavell, 2001). Furthermore, it inhibits the production of the important effector cytokine IFN-g in differentiated T-helper cells and, even more importantly, also negatively regulates the differentiation and proliferation of CTLs (Ludviksson et al., 2000). Furthermore TGF-b disarms CTLs by downregulating their effector molecules, perforin and CD95 ligand (Genestier et al., 1999; Ahmadzadeh and Rosenberg, 2005). The question of whether TGF-b might be able to generate tumorassociated Treg, which block potent immune responses, is still under discussion (Chen et al., 2003). The activation and cytolytic function of NK cells as another subset of lymphocytes are also affected by TGF-b. The activation of NK cells depends on a balance of signals mediated by inhibiting and activating receptors (Lanier, 2003). The most prominent activating NK-cell receptor investigated in the context of glioma is NKG2D, which can also provide costimulatory signals to CTLs. Triggering of NKG2D initiates a perforin-mediated cytolytic response against tumorigenic cells (Hayakawa et al., 2002). NKG2D interacts with different MHC class I homologous ligands (NKG2DL). In humans, these are MHC class I chain-related molecules A (MICA) and MICB, UL16-binding proteins (ULBP) 1–3, ULBP4/RAET1E and RAET1G (Cosman et al., 2001; Chalupny et al., 2003; Bacon et al., 2004). In pathological conditions such as brain tumors, NKG2DL expression is upregulated (Bauer et al., 1999; Das et al., 2001; Friese et al., 2003). NKG2DL are expressed in human gliomas in vivo and thus may label tumor cells for recognition by NKG2D-expressing immune effector cells. However, MICA and ULBP2 expression levels are downregulated towards baseline levels in glioblastomas (Eisele et al., 2006). In vitro TGF-b downregulates MICA and ULBP2 on glioma cells and also the NKG2D receptor on NK cells (Friese et al., 2004). Other activating NK-cell receptors such as NKp30, NKp40, and NKp46 are also partially downregulated by TGF-b (Castriconi et al., 2003). TGF-b inhibits the maturation of DCs and thereby promotes the formation of an immature phenotype of these cells (Yamaguchi et al., 1997). MHC class II molecules on DCs are downregulated by TGF-b, impairing their capacity for antigen presentation (Geissmann et al., 1999). Because of its various modes of action, TGF-b seems to be an attractive target for immunotherapeutic strategies. Several approaches, using TGF-b inhibitors and antisense strategies, have been used in glioma mouse models and have shown promising results (Jachimczak et al., 1993; Friese et al., 2004; Uhl et al., 2004).
48
P. ROTH ET AL.
Nonclassical major histocompatibility complex class I molecules As mentioned above, glioma cells show an intermediate expression level of classical MHC class I molecules that inhibit NK cell-mediated lysis by interacting with inhibitory killer immunoglobulin-like receptors (KIR). In contrast to these classical MHC molecules, the nonclassical MHC class I molecules (class Ib), human leukocyte antigen (HLA)-E and HLA-G, show an expression pattern that is limited to few tissues, such as placenta. However, in vitro and in vivo studies have confirmed their surface expression by glioma cells. HLA-E can hamper the killing efficacy of NK cells by interacting with its main receptor, CD94/NKG2A (Wischhusen et al., 2005). The inhibitory NKG2A receptor is also found on T cells, and its expression is upregulated by TGF-b (Bertone et al., 1999). HLA-G shows limited polymorphism and its alternatively spliced mRNA encodes at least seven different isoforms, including membrane-bound and soluble proteins. HLA-G acts as a ligand for several inhibitory immune cell receptors and inhibits, in particular, T-cell responses (Wiendl et al., 2002).
Further immunosuppressive factors During the past decade, numerous molecules have been identified as potential mediators of glioma-associated immunosuppression. One of the first was IL-10, a cytokine with immune modulatory properties that is released by malignant glioma cells. In vitro studies suggested that IL-10 interferes with immune cell-derived IFN-g and TNF-a, and downregulates MHC class II molecules (Hishii et al., 1995). It remains elusive whether these effects are important for the in vivo situation of glioma immunology. In addition, more than 10 years ago prostaglandin (PG) E2 was identified as a further glioma-derived molecule with immunosuppressive effects, and might shift T-cell development to a regulatory subtype (Lauro et al., 1986; Akasaki et al., 2004). T and NK cells can attack tumor cells by the expression of CD95 ligand. Reduced expression of its receptor CD95 on glioma cells and expression of the soluble decoy receptor 3 (DcR3), which lacks a transmembrane domain, result in a disruption of the CD95 ligand-dependent tumor cell attack. On the other hand, CD95 ligand is also expressed by malignant glioma cells. It can thereby induce apoptosis on CD95expressing cells of the immune system (Saas et al., 1997). Novel molecules that may contribute to the immunosuppressive phenotype of malignant glioma cells include B7 homolog 1 (B7-H1), regeneration and tolerance factor (RTF), and lectin-like transcript 1 (LLT1). The interaction of glioma-derived B7-H1 with
its receptor PD-1 inhibits T-cell responses (Wintterle et al., 2003). Interestingly, loss of the tumor suppressor phosphatase and tensin homolog (PTEN) leads to immunoresistance that is mediated by B7-H1 (Parsa et al., 2007). RTF exists as a transmembrane and a soluble protein that interacts with a so far unknown eceptor. It is massively overexpressed in malignant glioma cells compared with expression in normal human brain tissue. RTF expression by malignant glioma cells leads to impaired T- and NK-cell cytotoxicity (Roth et al., 2006). LLT1 is a novel ligand for the inhibitory NK-cell receptor CD161. Expression of LLT1 by glioma cells suppresses the killing efficiency of NK cells in vitro (Roth et al., 2007). CD70 is a tumor necrosis factor-related cell-surface ligand, and its receptor, CD27, is expressed on different immune cell populations. The role of CD70 in the immunobiology of malignant gliomas is rather controversial. CD70, expressed on the cell surface of glioma cells, induces B- and T-cell apoptosis in vitro (Wischhusen et al., 2002). However, in vivo studies using a syngeneic murine glioma model have suggested that the net effect of CD70 expression in gliomas is immunostimulatory rather than paralytic (Aulwurm et al., 2006). The role of the immune system in other tumor entities of the CNS, such as meningioma, ependymoma, and medulloblastoma, remains less clear. There are a few reports indicating a possible immunomodulatory function for these tumors (Kempuraj et al., 2004; Kumar et al., 2006). The same applies to brain metastases from other tumor entities. A few reports have suggested local immunosuppression in the brain by metastatic disease, but it has to be considered that patients with systemic tumors suffer from a general impairment of their immune system (Ohshima et al., 2003; Whiteside, 2006). Overall, the importance of these observations for prognosis and clinical practice, and for the development of immunotherapeutic strategies for the treatment of these tumors, has not yet been investigated sufficiently.
SUMMARYAND CONCLUSIONS Brain tumors of different origin, but notably malignant gliomas, are characterized by their immunosuppressive properties which allow them to escape the host’s immune surveillance. The activating immune cell ligands that are expressed by tumor cells, together with potentially immunogenic antigens, are overridden by numerous immune inhibitory signals, with TGF-b as the master immunosuppressive molecule (Figure 4.1). The ongoing investigation of mechanisms of tumorderived immunosuppression allows for an increasing understanding of brain tumor immunology. Targeting
IMMUNOLOGY OF BRAIN TUMORS MHC class I NKG2DL CD95 ligand
Glioma cells
TGF-b IL-10 PGE2 HLA-E HLA-G B7-H1 RTF
NK cells
NKG2D CD94/NKG2A Proliferation Cytotoxicity
IFN-g IL-2 NKG2D Proliferation T cells Cytotoxicity MHC class II CD80, CD86 Microglia
Antigen presentation
Fig. 4.1. Mediators of glioma-associated immunosuppression: immune inhibitory signals expressed by malignant glioma cells (black); autocrine effects (blue); and influence on different subpopulations of lymphocytes and microglial cells (red). For abbreviations and details see main text. (Adapted from Fenstermaker and Ciesielski (2004).)
different mechanisms of tumor-derived immunosuppression, such as inhibition of TGF-b, may represent a promising strategy for future immunotherapeutic approaches.
REFERENCES Ahmadzadeh M, Rosenberg SA (2005). TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol 174: 5215–5223. Akasaki Y, Liu G, Chung NH et al. (2004). Induction of a CD4þ T regulatory type 1 response by cyclooxygenase2-overexpressing glioma. J Immunol 173: 4352–4359. Aulwurm S, Wischhusen J, Friese M et al. (2006). Immune stimulatory effects of CD70 override CD70-mediated immune cell apoptosis in rodent glioma models and confer long-lasting antiglioma immunity in vivo. Int J Cancer 118: 1728–1735. Bacon L, Eagle RA, Meyer M et al. (2004). Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D. J Immunol 173: 1078–1084. Badie B, Schartner J (2001). Role of microglia in glioma biology. Microsc Res Tech 54: 106–113. Bauer S, Groh V, Wu J et al. (1999). Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285: 727–729. Bertone S, Schiavetti F, Bellomo R et al. (1999). Transforming growth factor-beta-induced expression of CD94/ NKG2A inhibitory receptors in human T lymphocytes. Eur J Immunol 29: 23–29. Castriconi R, Cantoni C, Della Chiesa M et al. (2003). Transforming growth factor beta 1 inhibits expression of nkp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 100: 4120–4125.
49
Chalupny NJ, Sutherland CL, Lawrence WA et al. (2003). ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun 305: 129–135. Chen W, Jin W, Hardegen N et al. (2003). Conversion of peripheral CD4þCD25 naive T cells to CD4þCD25þ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198: 1875–1886. Cosman D, Mullberg J, Sutherland CL et al. (2001). Ulbps, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14: 123–133. Das H, Groh V, Kuijl C et al. (2001). MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigendependent effector function. Immunity 15: 83–93. Doolittle ND, Abrey LE, Bleyer WA et al. (2005). New frontiers in translational research in neuro-oncology and the blood–brain barrier: report of the tenth annual Blood–Brain Barrier Disruption Consortium Meeting. Clin Cancer Res 11: 421–428. Eisele G, Wischhusen J, Mittelbronn M et al. (2006). TGFbeta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 129: 2416–2425. Facoetti A, Nano R, Zelini P et al. (2005). Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors. Clin Cancer Res 11: 8304–8311. Fecci PE, Mitchell DA, Whitesides JF et al. (2006). Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66: 3294–3302. Fenstermaker RA, Ciesielski MJ (2004). Immunotherapeutic strategies for malignant glioma. Cancer Control 11: 181–191. Friese MA, Platten M, Lutz SZ et al. (2003). MICA/NKG2Dmediated immunogene therapy of experimental gliomas. Cancer Res 63: 8996–9006. Friese MA, Wischhusen J, Wick W et al. (2004). RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res 64: 7596–7603. Geissmann F, Revy P, Regnault A et al. (1999). TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 162: 4567–4575. Genestier L, Kasibhatla S, Brunner T et al. (1999). Transforming growth factor beta1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc. J Exp Med 189: 231–239. Gomez GG, Kruse CA (2006). Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene Ther Mol Biol 10: 133–146. Gorelik L, Flavell RA (2001). Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7: 1118–1122. Govinden R, Bhoola KD (2003). Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther 98: 257–265. Grauer OM, Nierkens S, Bennink E et al. (2007). CD4þfoxp3þ regulatory T cells gradually accumulate in
50
P. ROTH ET AL.
gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int J Cancer 121: 95–105. Hayakawa Y, Kelly JM, Westwood JA et al. (2002). Cutting edge: tumor rejection mediated by NKG2D receptor– ligand interaction is dependent upon perforin. J Immunol 169: 5377–5381. Hickey WF, Hsu BL, Kimura H (1991). T-lymphocyte entry into the central nervous system. J Neurosci Res 28: 254–260. Hishii M, Nitta T, Ishida H et al. (1995). Human gliomaderived interleukin-10 inhibits antitumor immune responses in vitro. Neurosurgery 37: 1160–1166. Hussain SF, Yang D, Suki D et al. (2006). The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro-oncol 8: 261–279. Jachimczak P, Bogdahn U, Schneider J et al. (1993). The effect of transforming growth factor-beta 2-specific phosphorothioate-anti-sense oligodeoxynucleotides in reversing cellular immunosuppression in malignant glioma. J Neurosurg 78: 944–951. Jensen RL (1998). Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review. Surg Neurol 49: 189–195. Karman J, Ling C, Sandor M et al. (2004). Dendritic cells in the initiation of immune responses against central nervous system-derived antigens. Immunol Lett 92: 107–115. Kempuraj D, Devi RS, Madhappan B et al. (2004). T lymphocyte subsets and immunoglobulins in intracranial tumor patients before and after treatment, and based on histological type of tumors. Int J Immunopathol Pharmacol 17: 57–64. Kumar R, Kamdar D, Madden L et al. (2006). Th1/Th2 cytokine imbalance in meningioma, anaplastic astrocytoma and glioblastoma multiforme patients. Oncol Rep 15: 1513–1516. Lanier LL (2003). Natural killer cell receptor signaling. Curr Opin Immunol 15: 308–314. Lanier LL (2005). NK cell recognition. Annu Rev Immunol 23: 225–274. Lauro GM, Di Lorenzo N, Grossi M et al. (1986). Prostaglandin E2 as an immunomodulating factor released in vitro by human glioma cells. Acta Neuropathol (Berl) 69: 278–282. Leitlein J, Aulwurm S, Waltereit R et al. (2001). Processing of immunosuppressive pro-TGF-beta 1,2 by human glioblastoma cells involves cytoplasmic and secreted furinlike proteases. J Immunol 166: 7238–7243. Ludviksson BR, Seegers D, Resnick AS et al. (2000). The effect of TGF-beta1 on immune responses of naive versus memory CD4þ Th1/Th2 T cells. Eur J Immunol 30: 2101–2111. Ohshima K, Hamasaki M, Makimoto Y et al. (2003). Differential chemokine, chemokine receptor, cytokine and cytokine receptor expression in pulmonary adenocarcinoma: diffuse down-regulation is associated with immune evasion and brain metastasis. Int J Oncol 23: 965–973. Oklu R, Hesketh R (2000). The latent transforming growth factor beta binding protein (LTBP) family. Biochem J 352: 601–610.
Parney IF, Farr-Jones MA, Chang LJ et al. (2000a). Human glioma immunobiology in vitro: implications for immunogene therapy. Neurosurgery 46: 1169–1177. Parney IF, Hao C, Petruk KC (2000b). Glioma immunology and immunotherapy. Neurosurgery 46: 778–791. Parsa AT, Waldron JS, Panner A et al. (2007). Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13: 84–88. Platten M, Kretz A, Naumann U et al. (2003). Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann Neurol 54: 388–392. Roth P, Aulwurm S, Gekel I et al. (2006). Regeneration and tolerance factor: a novel mediator of glioblastoma-associated immunosuppression. Cancer Res 66: 3852–3858. Roth P, Mittelbronn M, Wick W et al. (2007). Malignant glioma cells counteract antitumor immune responses through expression of lectin-like transcript-1. Cancer Res 67: 3540–3544. Russell JH, Ley TJ (2002). Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 20: 323–370. Saas P, Walker PR, Hahne M et al. (1997). Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? J Clin Invest 99: 1173–1178. Saito T, Tanaka R, Yoshida S et al. (1988). Immunohistochemical analysis of tumor-infiltrating lymphocytes and major histocompatibility antigens in human gliomas and metastatic brain tumors. Surg Neurol 29: 435–442. Schartner JM, Hagar AR, Van Handel M et al. (2005). Impaired capacity for upregulation of MHC class II in tumor-associated microglia. Glia 51: 279–285. Schweitzer T, Vince GH, Herbold C et al. (2001). Extraneural metastases of primary brain tumors. J Neurooncol 53: 107–114. Shi Y, Massague J (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113: 685–700. Sikorski CW, Lesniak MS (2005). Immunotherapy for malignant glioma: current approaches and future directions. Neurol Res 27: 703–716. Streit WJ, Conde JR, Fendrick SE et al. (2005). Role of microglia in the central nervous system’s immune response. Neurol Res 27: 685–691. Uhl M, Aulwurm S, Wischhusen J et al. (2004). SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 64: 7954–7961. Watters JJ, Schartner JM, Badie B (2005). Microglia function in brain tumors. J Neurosci Res 81: 447–455. Whiteside TL (2006). Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Semin Cancer Biol 16: 3–15. Wick W, Naumann U, Weller M (2006). Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. Curr Pharm Des 12: 341–349. Wiendl H, Mitsdoerffer M, Hofmeister V et al. (2002). A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 168: 4772–4780.
IMMUNOLOGY OF BRAIN TUMORS Wintterle S, Schreiner B, Mitsdoerffer M et al. (2003). Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res 63: 7462–7467. Wischhusen J, Jung G, Radovanovic I et al. (2002). Identification of CD70-mediated apoptosis of immune effector cells as a novel immune escape pathway of human glioblastoma. Cancer Res 62: 2592–2599.
51
Wischhusen J, Friese MA, Mittelbronn M et al. (2005). HLAE protects glioma cells from NKG2D-mediated immune responses in vitro: implications for immune escape in vivo. J Neuropathol Exp Neurol 64: 523–528. Yamaguchi Y, Tsumura H, Miwa M et al. (1997). Contrasting effects of TGF-beta 1 and TNF-alpha on the development of dendritic cells from progenitors in mouse bone marrow. Stem Cells 15: 144–153.