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Page 2 of 14 Choi et al. Neuroimmunol Neuroinflammation 2018;5:42 I http://dx.doi.org/10.20517/2347-8659.2018.47

mounting anti-tumor immune responses against several types of cancers like non-small-cell lung cancer,
[1-5]
bladder cancer, and advanced-stage melanoma . Intrinsic to ICI-based therapies, particularly those
blocking cytotoxic T lymphocyte antigen 4 and programmed cell death protein 1 (PD-1), is the recruitment
+
of CD8 T cells from tumor infiltrating lymphocytes (TILs) that are normally immunosuppressed in
[6]
the tumor microenvironment (TME) . However, certain cancers have remained resistant to current
immunotherapeutic strategies and are considered “cold tumors”; the recent phase III CheckMate 143 trial
involving nivolumab, an anti-PD-1 drug, failed to meet its primary endpoint of improved overall survival in
[7,8]
patients with glioblastoma (GBM) .

GBM is the most aggressive intrinsic brain tumor, with median overall survival ranging from 12 to 15 months
[9]
in patients who receive current standard of care . While ICI has shown some promise in preclinical GBM
models - particularly in combination with radiation therapy - emerging studies support the idea that GBM
is a cold tumor, meaning that it shows more resistance to anti-PD-1 when compared to other hot tumors
like melanoma that respond to ICI therapies; in regards to this difference in response, GBM appears to
have a (1) T cell population with high expression of exhaustion markers such as lymphocyte-activation
gene 3 (LAG3/CD223) and T-cell immunoglobulin mucin 3 (TIM3); (2) relatively few TILs; and (3) a high
volume of myeloid cells (i.e., microglia and macrophages) that make up about 30%-40% of the tumor cell
population [10,11] .

As such, there is interest in exploring additional candidates for immune cell reactivation beyond
[12]
lymphocytes, particularly within the myeloid population . Along this line, several studies in the last decade
have revealed immunosuppressive and pro-tumor characteristics in microglia and macrophages within the
TME, resulting in a growing interest in viewing these myeloid cells as potential therapeutic targets [12-14] .
It should be noted that while granulocytic or monocytic myeloid-derived suppressor cells (MDSCs) are
also considered to be a part of the myeloid compartment, there is limited data regarding specific markers
that easily distinguish MDSCs from monocytes and will therefore not be addressed further as a distinct
[15]
population from microglia and macrophages at this time .

As such, the purpose of this review is to distinguish the structural and functional differences of microglia
and macrophages in the context of the TME of GBM, expand upon the roles of microglia and macrophages
in GBM progression and invasion, and discuss current and potential treatment strategies involving these two
cell populations.

Macrophages and microglia: similar but distinct populations
Historically, microglia and macrophages have generally been considered interchangeable in the TME, with
the former functionally described as the macrophages of the central nervous system (CNS). While both cell
types have shared immunologic functions, including phagocytosis of microorganisms and cell debris with
[16]
subsequent antigen presentation to lymphocytes , the advent of genome-wide microarray analyses and
detection of specific cellular markers have phenotypically distinguished these cell populations [Figure 1] [17,18] .

[20]
[19]
Moreover, embryological studies like those from Janossy et al. and Ginhoux et al. have shown that
[13]
microglia and macrophages come from distinct embryological origins [Figure 1A] . Microglia, which
[19]
are endemic to the CNS, come from yolk sac progenitors and migrate to the brain early in development .
The prevailing thought is that microglial populations are enduring and maintain their numbers primarily
[21]
through local self-renewal [13,20] . Recent fluorescent fate-mapping studies from Tay et al. support this model
and also suggest that this self-renewal process is stochastic in the normal steady-state, independent of bone
marrow (BM) input, and dependent upon brain geography and inflammatory status.

However, during states of CNS inflammation, BM-derived macrophages can be drawn into the CNS