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function [71, 78–80]. They suppress T cells with several mechanisms by relying

on the production of certain proteins and other chemicals. For instance, MD-

SCs can deplete T cell survival and function inducer amino acid, L-arginine,

in the environment by arginase 1 and promote tumor with S100A8/9 [72, 81].

Another important issue is the transfer of MDSC vesicles containing PD-L1

to convert B cells into immunosuppressive Bregs. After uptaking the vesicles,

these cells begin to express CD155, IL-10, and TGF-β, and have capability

to suppress effector CD8+ T cell activation and function [82]. Additionally,

PIGF signal changes naive B cells to TGF-β expressing Bregs to control T

cell behavior [83].

3.2.2

Extracellular Matrix (ECM) of Brain and GBM

Apart from cells, soft tissue of brain is contributed by interstitial system that

fills the gap between the cells. This system is composed of interstitial fluid

that bathes the surface of cells and an ECM for cellular functions necessary

for development, maintenance, and treatment efficiency. In GBM, important

features of this network are altered to serve for the tumor growth [84].

3D network of brain is primarily built on the arrangements of nonfibril-

lar and fibrillar proteins and composition differs within brain regions [85].

Besides, certain ECM structures are present in the brain: Neural interstitial

matrix, perineuronal nets (PNNs) and basement membrane of BBB (Fig-

ure 3.2). Neural interstitial matrix is a proteinous network occupying the

space of brain parenchyma. It is assembled into the interconnected web

of ECM through mainly hyaluronic acid, chondroitin sulfate proteoglycans

(CSPGs), tenascins and link proteins, at a small quantity of collagen, laminin,

fibronectin and elastin [86]. PNNs are a proteinous web covering neurons

as physical barrier managing diverse functions at neuron-neuron, neuron-

ECM interface [87]. They manage distribution of receptors such as AMPAR

on the cell surface at synaptic cleft and inhibit juvenile plasticity [88, 89],

protect against oxidative stress [90], act as reservoirs for cations [91], as

well as sequester plasticity-related (e.g. Sema3A) and PNN assembly-related

(e.g.Nptx2) molecules [92, 93]. These nets are rich in hyaluronic acid, proteo-

glycans, tenascins and link proteins [87, 94]. In contrast, basement membrane

is a sheet-like structure wrapping around the blood vessels and assists for-

mation of BBB for strict permeability control in/out of brain. This layer has

a distinct composition enriched with collagen, laminin, fibronectin, perlecan,

nidogen/entactin, and agrin [95, 96].

Considering the distribution of each protein and polysaccharide, their roles

in (patho)physiology of development and adults have taken significant at-

tention in basic research and clinics. It is proven non-cellular microenviron-

ment goes under significant modifications which eventually impose tumor-

promoting course in the prognosis and treatment for many brain diseases.

For instance, as a physical barrier, hyaluronic acid coating hinders GBM cells

so that it restricts immune surveillance and, therefore, halts immune attack.