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Dello Russo et al. Neuroimmunol Neuroinflammation 2018;5:36 I http://dx.doi.org/10.20517/2347-8659.2018.42 Page 3 of 13

[13]
DNA-methyltransferase promoter methylation . In fact, most glioblastoma tumors tend to recur after being
surgically removed. This is partly due to the highly infiltrative nature of these cancer cells, so that radical
surgery is difficult to achieve. On the other hand, tumors can regenerate from glioblastoma cancer stem cells
(GSCs) that are usually resistant to radio- and chemotherapy. Treatment guidelines for recurrent disease are
less defined and may include a second surgery, re-irradiation, or re-exposure to temozolomide at standard
dose. Other options comprise systemic chemotherapy with one nitrosourea drug, i.e., carmustine, lomus-
tine, or fotemustine, and in the United States, the monoclonal antibody against vascular endothelial growth
[13]
factor-A (VEGF-A) bevacizumab . Finally, several targeted therapies have been tested in clinical trials with
limited beneficial effects. Interestingly, we observed using primary cultures of rat microglial cells that temo-
zolomide did not reduce microglial cell viability after 24 h treatments in the µmol/L (clinically relevant) dose
[14]
range, albeit it significantly increased intracellular protein content . Notably, resistance to anti-angiogenic
therapy, i.e., bevacizumab, appears to be mediated by changes in the glioblastoma’s microenvironment, in-
cluding the extent of myeloid cell infiltration as well as their biological activities [15-17] . In preclinical models of
glioblastoma, it has been shown that ionizing radiations increase the recruitment of myeloid cells with a pro-
[18]
tumorigenic phenotype at the tumor site, contributing to disease recurrence . Taken together, the evidence
suggest a possible involvement of GAMs in the response to standard treatments. Therefore, glioma associ-
ated myeloid cells can be envisioned as an alternative or an ancillary pharmacological target to improve the
clinical outcome of current available therapies. Noteworthy, the glioblastoma microenvironment includes
also other immune cells, namely regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs),
that concur to the establishment of an immunosuppressive environment, impairing the effector function
[19]
of infiltrating T cells and natural killer cells and facilitating tumor growth . Therefore, a comprehensive
understanding of these different components of the patients’ immune system endowed in the tumor micro-
environment is necessary to develop therapeutic strategies that increase anti-tumor immunity and clinical
benefits. In the present paper, we aim at the revision of pharmacological strategies that interfere with GAMs’
function, i.e., cell recruitment at the tumor site, cell inflammatory activation and immune function, and the
extracellular matrix remodeling promoted by GAM-secreted factors. For recent advances on the biology of
MDSCs and Tregs in the glioblastoma microenvironment and their potential role as therapeutic targets, we
refer the readers to other review articles [20,21] .

DRUGS TARGETING GAMS’ FUNCTION FOR THE TREATMENT OF GLIOBLASTOMA
Drugs that interfere with GAMs’ recruitment at the tumor site
Microglial cells are recruited at the tumor site by several chemoattractant factors which are produced and
[4,5]
released by tumoral cells . One of the first identified GAMs’ chemoattractant factor is the hepatocyte
[22]
growth factor , which binds to and activates the tyrosine kinase receptor, c-Met. The latter plays a role both
[22]
on microglial motility and cell proliferation . Other glioma-released chemoattractant factors are the my-
[23]
eloid colony stimulating factors (CSFs), i.e., the macrophage colony stimulating factor (M-CSF or CSF1) ,
[24]
the granulocyte/macrophage colony stimulating factor (GM-CSF or CSF2) . These factors signal through
[25]
activation of two different receptors . The M-CSF receptor (CSF1R) is a homodimeric type III receptor,
encoded by the FMS proto-oncogene, with intrinsic tyrosine kinase activity, whereas the GM-CSF receptor
(CSF2R) is a heterodimer composed of a specific ligand-binding subunit (the α-chain) and a common β-chain.
The latter is the signal transduction subunit and is shared with the receptors for interleukin (IL)-3 and IL-
5. Activation of the CSF2R is known to stimulate at least three pathways: the Janus kinase-signal transducer
and activator of transcription (JAK-STAT) pathway, the mitogen-activated protein kinase (MAPK) pathway
[25]
and the phosphoinositide 3-kinase pathway . In addition, the monocyte chemotactic proteins (MCPs), par-
[28]
ticularly MCP-1/chemokine (C-C motif) ligand 2 (CCL2) [26,27] , and the stromal-derived factor-1 (SDF-1) , have
shown to play a role in the recruitment of microglial cells to the tumor site [Figure 1]. In addition a substan-
tial number of peripherally derived macrophages can be consistently detected in glioma GL261 implanted
[29]
tumors, since the early phases of disease . Once inside the tumors, GAMs usually acquire a specific pheno-
[30]
type of activation that favors tumor growth, angiogenesis and promotes the invasion of normal brain pa-