It has been demonstrated that patients diagnosed with GBM present with significant impaired immune function (23,24). The induction of potent and sustained antitumor immune responses in the immunocompetent host is extremely challenging due to intrinsic tumor tolerance mechanisms (5a). Studies have described tumor cells' ability to evade immune attack by using various strategies. Gomez and Kruse describe the various mechanisms of malignant glioma immune resistance and sources of immunosuppression (5a). We discuss their findings below.
Tumor cells produce immunosuppressive factors such as PGE2, TGF-p, and IL-10. PGE2 is a COX-2-derived prostaglandin E2 which promotes tumor cell invasion, motility, and angiogenesis upon binding to its receptor EPI-4 (5 a). PGE2 also induces immunosuppression by downregulating production of T helper TH1 cytokines (IL-2, IFN-g, and TNF-a) and upregulating TH2 cytokines (IL-4, IL-10, and IL-6) (25). PGE2 also inhibits T-cell activation and suppresses the antitumor activity of NK cells (26,27), and can enhance suppressive activity of Treg cells.
TGF-p is involved with regulating inflammation, angiogenesis, and proliferation (28), and is expressed by a variety of cancers including astrocytomas and appears to be the major isoform expressed by glioblastomas. TGF-p inhibits T-cell activation and proliferation (29,30), and maturation and function of professional APCs (31-33). TGF-p also inhibits synthesis of cytotoxic molecules including perforin, granzymes A and B, IFN-g, and FasL in activated cytotoxic T-lymphocyte (CTL) (32,33). TGF-p can facilitate conversion of naive T cells to a Treg phenotype, thereby playing a role in tumor tolerance and may recruit Tregs toward the primary tumor site as a means of immune evasion (5a). IL-10 inhibits IL-2-induced T-cell proliferation (34), DC, and macrophage activation of T cells (35), and downmodulates class II MHC on APCs and is expressed by Treg cells (8) and human gliomas (35).
In order to evade immune attack, tumor cells impair the adhesive effector between tumor cell interactions and protective tumor cloaks (5a). Tumor cells develop strategies to prevent their adhesion by immune effector cells. A mechanism of evasion from tumor-specific T and NK cell lysis is disruption of leukocyte function antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) interactions which inhibit target cell lysis (36,37).
MHC class I molecules, or HLA, are required for presentation of foreign antigen peptides to cytotoxic T cells and for the engagement of receptors that regulate NK-cell activity (38). The brain displays low or absent levels of MHC class I. Tumor cells can evade T-cell detection and subsequent induced cyto-toxicity if they display aberrant HLA class I expression (5a). Complete HLA class I loss may be caused by mutations of both p2-m alleles with the absence of p2-m expression; HLA class I heavy chain/p2-m/peptide complexes will not form nor be transported to the cell surface (5 a).
NK cells can kill cancer cells without prior sensitization. They are responsible for killing HLA class I-deficient tumor cells (38). In neoplastic conditions, HLA class I expression is often altered, breaking NK cell tolerance (5a). Ectopic HLA-G expression is a mechanism of tumor evasion of T and NK cell lysis (39) and is believed to protect the fetus from allorejection by maternal NK and T cells (5a). HLA-G is expressed on primary GBM and by established glioma cell lines (39). HLA-G expression causes glioma cells to be resistant to alloreactive CTL lysis and its inhibitory signals are strong enough to counteract NK-activating signals.
NK and activated T cells regulate tumor growth via the Fas apoptosis pathway; however, tumor cells may disrupt this pathway at many levels within the signaling cascade (5a). Disruption of Fas-induced apoptosis or upregulation of FasL may provide tumor-cell protection to T lymphocyte-induced cell injury (5a). Decoy receptor 3 (DcR3) is expressed by brain tumors and inhibits Fas-induced apoptosis (40,41). Decreased expression of Fas or secretion of FasL decoy receptor, DcR3, by glioma cells inhibits death receptor-induced apoptosis. Tumor cells can cause T-cell apoptosis when they counterattack T cells by expressing FasL which engages Fas on the T-cell plasma membrane (5a).
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