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Page 6 of 13 Dello Russo et al. Neuroimmunol Neuroinflammation 2018;5:36 I http://dx.doi.org/10.20517/2347-8659.2018.42

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tent C57BL/6 mice, against highly aggressive tumors derived from enriched stem-like CD133 GL261 glioma
cells. Notably, the antitumor effects of AmpB in vivo are achieved with lower doses than those maximally
tolerated in humans.

Another promising class of therapeutics for the treatment of glioblastoma are the inhibitors of the mecha-
nistic target of rapamycin (mTOR) kinase and/or other related kinases. The mTOR kinase is a central regu-
[54]
lator of several intracellular processes related to cellular growth, metabolism, and proliferation . Robust
evidence have highlighted the crucial role of this pathway in glioblastoma biology, together with the dem-
[55]
onstration of significant antiproliferative effects obtained by its pharmacological inhibition . Several drugs
[56]
targeting this activity are currently in clinical development for the treatment of different types of cancer ,
including those with an optimal pharmacokinetic profile for the treatment of glioblastoma [56,57] . Notably, we
have shown that inhibition of mTOR activity in rat microglial cells can promote their antitumor properties
[58]
while restricting pro-tumorigenic features . Therefore, mTOR inhibitors have the potential to target both
glioblastoma and GAMs’ functions. Similarly, the chemokine receptor C-C chemokine receptor type 5 (CCR5)
inhibitor maraviroc, in the same in vitro model, showed both direct antiproliferative activities on rat glioma
[59]
C6 cells together with immune modulatory actions on glioma stimulated rat microglial cultures .
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Interestingly, both glioma and infiltrating GAMs express the Ca -activated K channels (KCa3.1), whose
inhibition using 1-(2-chlorophenyl) diphenylmethyl-1H-pyrazole (TRAM-34) induced a switch of GAMs
[60]
toward a pro-inflammatory, antitumor phenotype . In addition, in vivo treatments with TRAM-34 signifi-
[60]
cantly decreased the extent of tumor growth in glioma-bearing mice . Moreover, stimulation of microglia
[61]
with pro-inflammatory IL-12 is associated with increased phagocytic activity . Consistently, intracranial
injection of a recombinant adeno-associated viral vector (rAAV2) encoding for IL-12 augmented the brain
levels of IL-12 and IFNγ in tumor-bearing animals, favoring microglial infiltration into the tumor and
restoring their antitumor functions. Increased immune activation of GAMs significantly reduced tumor
[62]
growth and prolonged animal survival time . Similarly, systemic administration of miR-142-6p, whose
expression level is consistently downregulated in GAMs, extended animal survival in different glioma mod-
els. These beneficial effects relied on reduced GAMs’ infiltration at the tumor site and increased antitumor
[63]
activities . Inhibition of the C-X-C chemokine receptor type 4 (CXCR4) by a newly synthetized receptor
antagonist, peptide R, reduced tumor growth, glioma cell invasiveness, and intratumor vessel formation
[64]
while directing GAMs’ immune activation toward a pro-inflammatory/antitumor phenotype . Notably,
SDF-1 suppression in a murine glioma resulted in delayed tumor growth and invasiveness, lower microvas-
cular density, and higher density of microglia/macrophages in non-hypoxic compared to hypoxic regions.
These findings suggest that tumor-secreted SDF-1 stimulates glioma invasiveness and recruitment of GAMs
[65]
towards hypoxic areas . In addition, it has been recently shown that the antitumor activity of vosaroxin, a
first in class cytotoxic agent that intercalates DNA and inhibits topoisomerase II, are also linked to increased
[66]
recruitment of myeloid cells at the tumor site together with an augmented pro-inflammatory activation .
Likewise, the antitumor effects of chlorogenic acid (5-caffeoylquinic acid) (CHA) found in pre-clinical mod-
els of glioblastoma were associated with increased antitumor immune activations of GAMs. CHA is phe-
[67]
nolic compound found in the human diet, in coffee, apples, pears and in green tea . Finally, a recent paper
describes the beneficial effects of a single chain antibody (X7Ab) directed against the chemokine receptor
ACKR3/CXCR7. Reduction of tumor growth and improved survival were observed in vivo in different pre-
clinical models of glioblastoma, particularly when X7Ab was used in combination with standard doses of te-
mozolomide. Interestingly, increased mean fluorescence intensity of classical activated (major histocompat-
+
ibility complex class II, MHCII ) tumor infiltrating macrophages was detected, suggesting augmented pro-
[68]
inflammatory (i.e., antitumor) activation of these cells within the tumor microenvironment .
Drugs that interfere with matrix remodeling promoted by GAM-secreted factors
Besides their immune functions which may either restrict or favor astrocyte malignant transformation,