Babu and Adamson microglial density to differ by up to one order of magnitude in various brain regions, response to immunotherapies may also be location-dependent.51 In addition to the barriers posed by the normal brain, GBM cells elicit responses that often make development of treatments challenging (Figure 2). Patients with GBM have been shown to have systemic immune deficits, with lymphopenia of natural killer (NK) and CD4+ T cells, and dysregulation of cytokine profiles.52–56 Additionally, leukocyte impairments have been reported including decreased T- and B-cell proliferation, antigen presentation, cytokine and antibody production, and NK cell cytotoxicity. These effects are thought to be partly due to the secretion of molecules such as transfor ming g rowth factor-β (TGF-β), interleukin-10 (IL-10), prostaglandin E2 (PGE2), and gangliosides.57 Additionally, GBM cells express a multitude of immunosuppressive molecules, preventing the anti-tumor activity of leukocytes. The expression of the co-stimulatory inhibitory molecule B7-H1 on GBM-associated cancer-initiating cells triggers T cell apoptosis.58,59 HLA-G, a nonclassical MHC class I molecule, is also expressed on GBM cells and can prevent the efficient priming of cytotoxic T cells, inhibit alloproliferative responses, and increase resistance to alloreactive lysis.60 Similarly, the expression of CD70 on GBM cells results Dovepress in T- and B-cell apoptosis via the interaction with CD27.61 Another contributor to immunosuppression in patients with GBM is the increased levels of CD4+/CD25+ Tregs despite systemic lymphopenia.62 These cells are attracted to the tumor environment in high-grade astrocytic tumors due to the secretion of CCL2, and result in the inhibition of T cell cytokine secretion and proliferation.63–65 As a multitude of mechanisms contribute to immunosuppression in patients with GBM, a multimodal approach is necessary to reduce the immunosuppressive effects of the tumor microenvironment, and enhance the ability to mount an effective immune response within the CNS. EGFRvIII as an immunotherapeutic target EGFR is a transmembrane glycoprotein which contains an extracellular ligand-binding domain and a cytoplasmic domain containing a tyrosine kinase.66 It is activated upon binding of its ligands including the epidermal growth factor (EGF) or TGFα, resulting in receptor dimerization and activation of the tyrosine kinase domain. This turns on oncogenic pathways which may account for the poorer survival seen in GBM patients with EGFR amplification.67 This amplification and resulting overexpression of the EGFR protein is the most common genetic alteration in GBM, occurring in approximately 40% of Inhibit alloproliferative responses Resistance to alloreactive lysis Prevent T cell priming Induction of T-cell apoptosis Gangliosides HLA-G PGE-2 CCL2 Cell membrane IL-10 AttracectllssTreg TGF-B B7-H1 CD70 T-cell apoptosis T and B cell apoptosis Promote Treg activity Decreased antigen Inhibition of T and NK presentation cell cytotoxicity Inhibition of T and NK cell proliferation Figure 2 Various immunosuppressive factors expressed and secreted by glioblastoma cells. 96 submit your manuscript | www.dovepress.com Dovepress Core Evidence 2012:7