ARTICLE IN PRESS

Cancer Letters ■■ (2015) ■■–■■

Contents lists available at ScienceDirect

Cancer Letters
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

Expansion and functions of myeloid-derived suppressor cells in the

tumor microenvironment
Peng Qu, Li-zhen Wang, P. Charles Lin *
National Cancer Institute, National Institutes of Health, Frederick, MD, USA

A R T I C L E I N F O A B S T R A C T

Keywords:
Myeloid derived suppressor cells (MDSCs) are a group of immature myeloid cells accumulated in most
Myeloid-derived suppressor cells
cancer patients and mouse tumor models. MDSCs suppress host immune response and concurrently
Tumor microenvironment
angiogenesis
promote tumor angiogenesis, thereby promote tumor growth and progression. In this review, we discuss
immune suppression recent progresses in expansion and activity of tumor MDSCs, and describe new findings about immu-
M-MDSC nosuppressive function of different subtypes of MDSCs in cancer. We also discussed tumor angiogenic
PMN-MDSC activities and pro-tumor invasion/metastatic roles of MDSCs in tumor progression.
© 2015 Published by Elsevier Ireland Ltd.

Introduction
MDSCs are heterogeneous population of myeloid lineage cells
including myeloid progenitors and immature myeloid cells (IMCs).
MDSCs are highly increased in humans and mouse models with
various pathological disorders. They exert potent immune-
suppressive functions and are important negative regulators of
immune responses in chronic inflammation and cancer [1–3]. In
various cancer patients, MDSCs might be used as a prognostic marker
and potential therapeutic targets toward elimination of their im-
munosuppressive activity and enhancement of anti-tumor immune
responses [4–7].
MDSCs are defined as Gr-1 + CD11b+ cells in mice. They are further
divided into two subsets using antibodies that distinguish between
Ly-6C and Ly-6G: co-expression of CD11b with Ly-6G+/Ly-6Chigh as
monocytic lineage cells (M-MDSCs) whereas CD11b with Ly-6G+/
Ly-6Clow as granulocytic lineage cells (PMN-MDSCs). Both subsets
are elevated in tumor-bearing mice, although the higher increase
is primarily observed in PMN-MDSCs [8]. In humans, three sub-
groups of MDSCs have been reported on the basis of their ability
to mediate immune suppression using a variety of different
markers such as CD11b, CD14 and CD33. Human PMN-MDSCs
are CD14-CD11b + CD33 + CD15+, and human M-MDSCs are
CD14 + HLA-DR-/low cells. The third sub group of human MDSCs is
Lin-HLA-DR-CD33+ cells [9]. Human MDSCs are enumerated pri-
marily in peripheral blood from cancer patients and characterized
by immature myeloid cell surface markers. On the other hand, the
markers for murine MDSC are CD11b and Gr-1. Murine MDSCs have
* Corresponding author. Tel.: +1 301 228 4688; fax: +1 301 846 7017.
E-mail address: p.lin@nih.gov (P.C. Lin).
been studied in the context of peripheral circulation, spleen and bone
marrow from tumor mouse models [10].
Expansion and activation of MDSCs in tumor bearing hosts
MDSCs are highly elevated in cancer patients as well as tumor
bearing animal models. They possess strong immune suppressive
activities. What regulates MDSC expansion and activation in tumor
conditions is an important question that has been investigated ex-
tensively in the past. Studies have shown that many secreted factors,
such as growth factors and microbial products, are released in the
tumor microenvironments. These factors activate the expansion or
production of MDSCs [11]. Among them, granulocyte-macrophage
colony stimulating factor (GM-CSF), G-CSF, IL-6, prostaglandin-E2
(PGE2), cyclooxygenase 2 (Cox2) and VEGF seem to play a major role
[12–17]. Accordingly, clinical studies demonstrate that the numbers
of CD45 + lin−HLA-DR− human MDSCs decrease with a treatment
of bevacizumab, a monoclonal antibody directed against VEGF-A,
on patients with lung, breast and colorectal cancers [18]. Cytokines
inducing MDSCs acted on a common molecular pathway and the
immune-regulatory activity of both tumor-induced and BM-
derived MDSCs is shown entirely dependent on the C/EBPβ
transcription factor [10].
Some of these factors activate STAT transcription factors (STAT3,
STAT5, STAT6) in MDSCs, which function as important signal trans-
ducers in the expansion and activation of MDSCs [19]. The
development of MDSCs is also regulated by interferon regulatory
factor 8 (IRF-8). MDSC-inducing factors such as G-CSF and GM-
CSF downregulate IRF-8 via STAT3- and STAT5-dependent pathways.
The levels of IRF-8 in MDSCs in cancer patients decline with in-
creasing MDSC frequency, implicating IRF-8 as a negative regulator
in human MDSC biology [19]. Our studies also support the impor-
tance of STAT3 in MDSC expansion. We show that myeloid specific

http://dx.doi.org/10.1016/j.canlet.2015.10.022
0304-3835/© 2015 Published by Elsevier Ireland Ltd.

Please cite this article in press as: Peng Qu, Li-zhen Wang, P. Charles Lin, Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment, Cancer Letters
(2015), doi: 10.1016/j.canlet.2015.10.022
 ARTICLE IN PRESS
2 P. Qu et al./Cancer Letters ■■ (2015) ■■–■■
expression of either apoptosis inhibitor 6 (Api6) or metalloprotease-
12 (MMP12) activates STAT3 in these cells and consequently leads
to systemic expansion of MDSCs. Inhibition of STAT3 in vitro abol-
ishes the proliferation and suppressive activity of MDSCs [20,21].
Moreover, factors that promote myeloid-lineage cell differentia-
tion reduce MDSC population expansion [22]. A growing number
of studies have demonstrated a strong correlation between the levels
of MDSCs in blood of cancer patients and tumor stage and meta-
static status [23–25].
Regulatory functions of MDSCs in the tumor
microenvironment
The pro tumor functions of MDSCs are at least two folds: (1)
immune suppression through inhibition of functional T cells and
NK cells as well as induction of Treg expansion; (2) promoting tumor
angiogenesis and tumor invasion/metastasis via production of an-
giogenic factors and proteases in tumor tissues.
Immune suppressive activities of MDSCs
As reflected in its name, a major function of MDSC is potent
immune suppressive activity via targeting other immune cells, such
as T cells in tumor conditions [26–30]. MDSCs also suppress pro-
liferation and cytokine secretion in both T lymphocytes and Natural
Killer (NK) cells, as well as induction of apoptosis in T cell subsets
[31]. Many factors have been implicated in MDSC-mediated immune
suppression, including inducible nitric oxide synthase (iNOS),
arginase-1 (Arg1), Cox-2, PGE2 and TGF-β [32–35]. MDSCs deliver
the suppressive functions through a combination of multiple
molecules.
In general, PMN-MDSCs are more prevalent in the tumor mi-
croenvironment, however, M-MDSCs have much stronger immune
suppressive activity [9]. The suppressive function of M-MDSCs is
associated with the metabolism of L-arginine. Both Arg1 and iNOS
use L-arginine as a common substrate to produce urea or NO that
blocks T cell proliferation, differentiation and cytokine production
[33]. In addition to direct signaling effects through NO, iNOS can
also decreases the available levels of its substrate L-arginine, a process
that can be further accelerated by the metabolic activities of Arg-
1. Up-regulation of Arg1 activity leads to a depletion of L-arginine
from the pathological microenvironment, which leads to a reduc-
tion of TCR expression and T cell proliferation [36]. This metabolic
targeting is not unique to L-arginine, and studies have identified ad-
ditional metabolic targets utilized in MDSC-mediated immune
suppression, such as cystine and cysteine [37]. Moreover, M-MDSCs
are also capable of differentiating into tumor associated mac-
rophages (TAMs), which promote T cell apoptosis and lead to
immune suppression [9]. Both M-MDSCs and TAMs suppress CD8+
T cell functions in a non-specific manner at the tumor site. M-MDSCs
produce high levels of Arg1 and NO, whereas TAMs up-regulate the
expression of either Arg1 or iNOS, but not of both proteins, depen-
dent on the tumor microenvironment [38]. TAMs also inhibit T cell
function by secreting cytokines such as IL-1β and TGF-β [39] (Fig. 1).
PMN-MDSCs utilize various mechanisms to subdue the host
immune response. They produce TGF-β, a potent immune suppres-
sor [34,40]. PMN-MDSCs also have the ability to suppress immune
responses in an antigen-specific manner. They can take up, process
and present antigens to antigen-specific T cells [1]. Or through cell–
cell contact, PMN-MDSCs induce nitration of T-cell receptors (TCR),
which makes T cells unresponsive to antigen stimulation [11]. ROS
is another major factor responsible for PMN-MDSCs mediated
immune suppression. Inhibition of ROS production using an up-
stream inhibitor abolished PMN-MDSC mediated suppression in vitro
[41]. The combination of ROS and NO suppresses CD8+ T cell re-
sponses by producing peroxynitrite, which resulted in nitration of
Please cite this article in press as: Peng Qu, Li-zhen Wang, P. Charles Lin, Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment, Cancer Letters
(2015), doi: 10.1016/j.canlet.2015.10.022
Fig. 1. The regulation mechanisms of MDSCs in the tumor microenvironment. PMN-
MDSCs can take up, process and present antigens to antigen-specific T cells. Through
cell–cell contact, PMN-MDSCs induce nitration of the T-cell receptors (TCR) on the
surface of T cells. T cells become unresponsive to antigen specific stimulation.
M-MDSCs are differentiated into tumor associated macrophages (TAM) that inhibit
T and NK cell immune responses. Both PMN-MDSCs and M-MDSCs produce reac-
tive oxygen species (ROS) and nitric oxide (NO) which inhibit T and NK cells in a
non-specific manner. MDSCs induce Treg expansion via secretion of IL-10 and TGF-
β. In some cancer models, the induction of Treg by MDSCs is associated with the
expression of cytotoxic lymphocyte antigen 4 (CTLA4). Tregs inhibit T and NK cells.
MDSCs contribute to tumor angiogenesis by production of factors such as MMP9,
CCL2, VEGF and BV8. TGF-β signaling in MDSCs plays an important role in tumor
metastasis.
TCR and inhibition of TCR signaling [42]. PMN-MDSCs also down-
regulate the ζ chain of TCR to suppress T cell function [43].
Moreover, MDSCs induce Tregs expansion to promote tumor pro-
gression through different mechanisms in various tumor models.
In an ovarian cancer model, the induction of Tregs by MDSCs is as-
sociated with the expression of cytotoxic lymphocyte 4 antigen
(CTLA4), while MDSCs induce Treg expansion via secretion of
IL-10/TGF-β in colon tumor models [44]. Studies also find that ex-
pression of the immune stimulatory receptor CD40 on MDSCs is
required for MDSCs to suppress T-cell and induce Treg accumula-
tion in tumor models [9,45]. MDSC can directly impact on the
prevalence of Tregs through IFNγ dependent production of IL-10 or
iNOS [46]. Thus, MDSCs participate in both the control of T cell re-
sponses and the induction of Tregs capable of potentiating long-
term immune suppression.
Tumor angiogenic and pro-tumor invasion/metastatic activities of
MDSCs
In addition to suppressing host immune functions within the
tumor microenvironment, MDSCs also promote invasion and me-
tastasis of tumor cells. In tumor-bearing hosts, MDSCs are increased
in lymph organs or in other organs, including lungs and livers, where
MDSCs could facilitate tumor metastasis to these organ sites [10,47].
Preclinical evidence has shown that hypoxic breast cancer cells
produce carbonic anhydrase IX (CAIX) and G-CSF to drive mobili-
zation of PMN-MDSCs to the breast cancer lung metastatic niches
[48].
It was found that the TGF-β signaling pathway is associated with
tumor cell motility, invasion and metastasis [49]. MDSCs produce
large numbers of MMPs and TGF-β1, which has a profound impact
on tumor progression and metastasis through modulation of tumor
vascularization and tumor cell invasion. TGF-β signaling in MDSCs
of tumor-bearing hosts is fundamentally important for tumor me-
tastasis. In a breast cancer mouse model, treatment with TGF-β
 ARTICLE IN PRESS
P. Qu et al./Cancer Letters ■■ (2015) ■■–■■
neutralization antibody significantly decreased the number of MDSCs
in tumor tissues and premetastatic lung through induction of MDSCs
apoptosis [50]. Genetic deletion of Tgfbr2 specifically in MDSCs dra-
matically blocks their suppressive functions and decreases tumor
metastasis (Fig. 1) [51–53]. Interestingly, enhanced metastasis in the
absence of tumor cell response to TGF- β stimulation has been shown
to involve increased chemokine production resulting in recruit-
ment of pro-metastatic MDSCs to the tumor microenvironment at
the leading invasive edge [54]. These data suggest that TGF- β is a
major regulator in MDSCs-mediated pro-metastasis in the tumor
microenvironment.
Additionally, MDSCs secrete factors to promote tumor angio-
genesis, a step essential for tumor growth and progression [55]. The
pro-angiogenic function of MDSCs is mediated in part through in-
duction of MMP9, a protease that degrades extracellular matrix
(ECM). As a result, it frees VEGF deposited in the matrix, which leads
to activation of VEGF receptors on endothelium and angiogenesis
[55]. Activation of STAT3 in MDSCs increases the production of VEGF
and FGF, both of which are potent angiogenic factors and pro-
motes tumor angiogenesis [56]. Studies have examined the
mechanisms of tumor refractoriness to VEGF blockade in synge-
neic mouse tumor models. Interestingly, MDSCs mediated
angiogenesis contributes to refractoriness to anti-VEGF tumor therapy
in mouse models [9,57,58]. Our results reveal that MDSCs in the
tumor microenvironment produced CCL2, which is known to func-
tion as an angiogenic factor. Blocking CCL2 produced by MDSCs led
to decreased endothelial cell migration [59]. Together, these studies
suggest that MDSCs promote tumor angiogenesis by production of
factors that alter the tumor microenvironment in a pro-angiogenic
manner (Fig. 1).
Emerging role of miRNA in MDSC biology
There is emerging evidence that microRNAs (miRNAs) play im-
portant roles in the activation and function of MDSCs. miRNAs are
small non-coding RNA molecules which are conserved in eukary-
otic organisms and are paired with complementary sequences within
mRNA molecules, thus resulting in translational repression or target
degradation [60–62]. Studies have identified many miRNAs, includ-
ing miR-17-5p, miR-20a, miR-21, miR-494, miR-125b, miR-155, miR-
223 and miR-146a, which target transcription factors important for
the development and differentiation of MDSCs [63,64].
A study shows that both miR-17-5p and miR-20a promote the
suppressive function of PMN-MDSCs, but not M-MDSCs, through
targeting STAT3 [65]. Tumor-associated factors downregulate the
expression of miR-17-5p and miR-20a, and consequently enhance
the suppressive function of PMN-MDSCs. Thus, miR-17-5p and miR-
20a might potentially be useful targets in immunotherapeutic
strategies to inhibit PMN-MDSCs via reducing STAT3 expression. The
roles of miR-155 and miR-21 on MDSCs are also associated with
STAT3 activation via targeting SHIP-1 and PTEN, respectively [66].
Even though those miRNAs regulate MDSC properties to create a
microenvironment suitable for cancer formation and develop-
ment, most of our knowledge of miRNA on MDSCs comes from
murine studies. There is limited clinical information about the role
and regulation of miRNA on MDSCs in cancer patients. The signif-
icance of miRNAs for the expansion and function of MDSCs in cancer
patients are largely unknown and hence require further investiga-
tion [67].
Conclusion
MDSCs are heterogeneous myeloid cells that are highly el-
evated in cancer patients and tumor bearing animal models. These
cells promote tumor growth and progression through immune sup-
pression as well as enhanced tumor angiogenesis and invasion/
Please cite this article in press as: Peng Qu, Li-zhen Wang, P. Charles Lin, Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment, Cancer Letters
(2015), doi: 10.1016/j.canlet.2015.10.022
3
metastasis. Targeting MDSCs may offer a therapeutic approach to
cancer patients.
Acknowledgment
The work was supported by the Intramural Research Program
at the NCI, NIH.
Conflict of interest
The authors declare no competing financial interests.
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