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Bioinformatics of the Brain

counterattack, signaling through released molecules such as IDO, TGF-β,

and IL-10, as well as cell-cell contact with GBM cells disable NK cells. For

instance, glioma cells express LLT1 as a protection mechanism against NK-

mediated lysis. This molecule interacts with CD161 receptor on NK cells to

block cytotoxicity and diminish IFN-γ expression [55–57].

When normal brain switches into tumor-promoting environment, anti-

tumor activity of dendritic cells and T cells are severely affected. Dendritic

cells mainly function in antigen presentation to T cells and secrete IFN-γ

[58]. Combination of secreted IL-2 by CD4+ T cells with antigen presen-

tation provokes CD8+ T cells to begin anti-tumor attack through perforin

and granzyme, as well as by secreting TNF-α, IFN-γ, and TRAIL [59, 60].

However, CTLA-4 of Tregs interacts with CD80/86 coreceptor of dendritic

cells to deplete it by trogocytosis so that these cells can no longer activate T

cells leading to escape of tumor cells from immune-screening [61]. Other Treg-

based mechanisms committed to tumor survival include inhibition of T cells

by lL-17 [62] and management of glioma stemness through TGF‑β–NF‑κB–

IL6–STAT3 pathway [63]. TGF-β also diminishes effector T cell survival and

function, as it has been reported that especially TGF-β-based immunoreg-

ulation halts expression of the soluble or membrane-bound proteins such as

perforin, granzyme, Fas-L, IFN-γ, and IL-2 [64, 65]. Another favorable aspect

of Treg activity depends on CD39 enzyme on Treg membrane in which this

enzyme converts ATP to AMP starting the cascade of adenosine formation

by CD73 of glioma cells. This adenosine binds to Aa2R on T cells to inhibit

its activity, directs macrophage fate to M2 phenotype and switches on Treg

production [66]. To do so, recruitment of Tregs to the site of brain tumors is

contributed by soluble factors such as CCL2 [67, 68], IDO [69], CCL28 [70],

and TGF-β [71]. Activation of Tregs through TGF-β and IL-10 by MDSC also

advances pro-tumor status [72]. By conferring aforementioned tumor promot-

ing actions in GBM development, Tregs are reported to be associated with

poor glioma patient survival [67].

Under physiological conditions, mast cells recruit and stimulate neu-

trophils, promote wound healing and fibrosis, react against allergens, carry

neuroimmune interactions and, function in blood coagulation and vascular

permeability [73]. In GBM, mast cells are mobilized towards tumor mass by

CXCL12, PAI-1 and MIF of tumor cells [74, 75]. Upon trigger, mast cells cause

inflammation and apoptosis of tumors, but also promote immunosuppression

and produce representative factors in Figure 3.1 to guide blood vessel cells

and promote angiogenesis in cancer [76, 77].

The existence of other cell groups such as myeloid derived suppressor cells

(MDSCs) also determines whether pro- or anti-tumor course will progress.

MDSCs are mixed population of bone-marrow derived immune system cells

accumulating in blood and tumor of glioma patients. These cells are reported

to be drawn to and activated by the tumors where they proliferate and ex-

ert many activities including suppression of effector T cells, development

of Tregs, induction M2 phenotype of macrophages and control of NK cell