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Coordinated regulation of myeloid
cells by tumours
Dmitry I. Gabrilovich1, Suzanne Ostrand-Rosenberg2 and Vincenzo Bronte3
Abstract | Myeloid cells are the most abundant nucleated haematopoietic cells in the human
body and are a collection of distinct cell populations with many diverse functions. The three
groups of terminally differentiated myeloid cells — macrophages, dendritic cells and
granulocytes — are essential for the normal function of both the innate and adaptive
immune systems. Mounting evidence indicates that the tumour microenvironment alters
myeloid cells and can convert them into potent immunosuppressive cells. Here, we consider
myeloid cells as an intricately connected, complex, single system and we focus on how
tumours manipulate the myeloid system to evade the host immune response.
Myeloid-derived suppressor
cells
(MDSCs). A group of immature
CD11b+GR1+ cells that
includes precursors of
macrophages, granulocytes,
dendritic cells and myeloid
cells. These cells are produced
in response to various
tumour-derived cytokines and
have been shown to inhibit
tumour-specific immune
responses.
H. Lee Moffitt Cancer Center
and Research Institute,
12902 Magnolia Drive,
Tampa, Florida 33647, USA.
2
University of Maryland
Baltimore County, 1000
Hilltop Circle, Baltimore,
Maryland 21250, USA.
3
Verona University,
P. le L.A. Scuro 10,
37134 Verona, Italy.
e-mails: dmitry.gabrilovich@
moffitt.org;
[email protected];
[email protected]
doi:10.1038/nri3175
1
Myeloid cells are the most abundant haematopoietic
cells in the human body and have diverse functions. All
myeloid cells arise from multipotent haematopoietic
stem cells (HSCs) that develop into mature myeloid cells
through sequential steps of differentiation. However,
myeloid progenitors do not form a hierarchical system
but can instead be considered as a network of cells that
can differentiate into various subsets of more-specialized
myeloid cells (FIG. 1).
The three groups of terminally differentiated myeloid cells — macrophages, dendritic cells (DCs) and
granulocytes — are essential for the normal functions
of the innate and adaptive immune systems. Classically,
these cells protect organisms from pathogens, eliminate
dying cells and mediate tissue remodelling. Although
the contribution of myeloid cells to tumour pathogenesis has been recognized for over 100 years, only during
the past two decades has their crucial role in promoting
tumour angiogenesis, cell invasion and metastasis been
appreciated (reviewed in REFS 1–3). Mast cells have also
been implicated in the regulation of tumour progression (reviewed in REF. 4). Mounting evidence indicates
that the tumour microenvironment alters myeloid cells
by converting them into potent immunosuppressive
cells. In recent years the concept of myeloid-derived suppressor cells (MDSCs) (described below) has emerged.
However, the wealth of new information concerning
myeloid cells in cancer has also produced confusion. In
most studies, individual myeloid cell populations have
been examined independently, generating fragmented
information that has contributed to a disjointed view of
the role of myeloid cells in immune responses in cancer.
In addition, their overlapping expression of cell-surface
markers has made it difficult to distinguish between
different myeloid cell populations, further obscuring
the nature of specific myeloid cell subsets in cancer.
These complications limit our understanding of myeloid cell biology and hamper attempts to develop and
optimize therapeutic interventions.
In this Review, we present a cohesive view of the
effects of tumours on myeloid cells. Our goal is not to
provide a comprehensive overview of the changes in
individual populations of myeloid cells, as this has been
accomplished in other recent reviews. Instead, we briefly
summarize the effects that tumours have on terminally
differentiated myeloid cell subsets and then focus on discussing myeloid cell interactions and responses during
tumour development as an intricately connected, single
(albeit complex) system.
Dendritic cells
DCs are terminally differentiated myeloid cells that
specialize in antigen processing and presentation. DCs
differentiate in the bone marrow from various progenitors5–8. They can also differentiate from monocytes
under certain conditions, although most DCs in mouse
lymphoid organs are not derived from monocytes5,9. By
contrast, monocytes are the major precursors of DCs in
humans10.
Two major subsets of DCs are currently recognized: conventional DCs (cDCs) and plasmacytoid
DCs (pDCs). Although these cells share some common progenitors, their differentiation is controlled by
distinct genetic programmes and they have different
morphologies, markers and functions11 (TABLE 1). The
centrepiece of DC biology is the concept of functional
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Lymphoid cells
HSC
T cell
CLP
B cell
MPP
CMLP
NK cell
Megakaryocyte
Granulocytes
MEP
GMP
CMP
Basophil
Eosinsophil
Erythrocytes
MCP
MDP
Mast cell
Monocyte
Macrophage
CDP
cDC
Neutrophil
pDC
Figure 1 | Myeloid cell differentiation under normal physiological conditions.
Myeloid cells originate from haematopoietic stem cells (HSCs)
multipotent
Natureand
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| Immunology
progenitor cells (MPPs). The figure illustrates the network of progenitor cells that
gives rise to the various haematopoietic cell lineages. cDC, conventional DC;
CDP, common DC progenitor; CLP, common lymphoid progenitor; CMLP, common
myelolymphoid progenitor; CMP, common myeloid progenitor; DC, dendritic cell;
GMP, granulocyte and macrophage progenitor; MCP, mast cell progenitor;
MDP, macrophage and DC progenitor; MEP, megakaryocyte and erythroid progenitor;
NK, natural killer; pDC, plasmacytoid DC.
Pathogen-associated
molecular patterns
(PAMPs). These are molecular
motifs that are found in
pathogens but not in
mammalian cells. Examples
include terminally
mannosylated and
polymannosylated
compounds, which bind to the
mannose receptor CD206, and
various microbial products that
activate host Toll-like receptors,
such as bacterial lipopolysaccharides, hypomethylated
DNA, flagellin and
double-stranded RNA.
activation and maturation in response to ‘dangerous’ stimuli. Differentiated DCs reside in tissues as
‘immature’ cells that actively take up tissue antigens but
are poor antigen presenters and do not promote effector T cell differentiation. Only functionally activated
DCs can effectively stimulate immune responses. DCs
are activated in response to stimuli associated with
bacteria, viruses or damaged tissues; such stimuli are
commonly referred to as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular
patterns (DAMPs).
The activation of DCs leads to profound changes in
their gene expression, resulting in increased expression
of co-stimulatory molecules and cytokines that promote T cell activation and also in the upregulation of
chemokine receptors that drive the migration of DCs to
lymphoid tissues. pDCs constitute a minor population
of DCs; they have a morphology reminiscent of plasma
cells, express Toll-like receptor 7 (TLR7) and TLR9 (this
receptor is not expressed by human cDCs) and produce
large amounts of interferon-α (IFNα) in response to the
activation of their TLRs by viral nucleic acids or self
DNA11. A more detailed discussion of DC biology can
be found in recent reviews9,12.
Effects of cancer on DCs. That cancer can have profound
effects on the function of DCs has been known for more
than 20 years. It is well established that DCs in tumourbearing hosts do not adequately stimulate an immune
response, and this potentially contributes to tumour evasion of immune recognition. Evidence from numerous
studies strongly indicates that abnormal myelopoiesis
is the dominant mechanism responsible for DC defects
in cancer 13. This abnormal differentiation produces at
least three main results: decreased production of mature
functionally competent DCs; increased accumulation of
immature DCs at the tumour site; and increased production of immature myeloid cells13. In recent years,
multiple clinical studies have confirmed the findings of
earlier studies and have indicated that there is a decreased
presence and defective functionality of mature DCs in
patients with breast 14, non-small cell lung 15, pancreatic16,
cervical17, hepatocellular 18 or prostate cancer, or glioma19.
In addition to the many tumour-derived soluble factors previously implicated in abnormal DC differentiation, such as vascular endothelial growth factor (VEGF),
macrophage colony-stimulating factor (M-CSF) and
interleukin‑6 (IL‑6), recent studies have shown that other
factors present in the tumour microenvironment impair
normal DC functions. The tumour microenvironment is
predominantly characterized by hypoxia, accumulation
of extracellular adenosine, increased levels of lactate and
a decreased pH. DC migration and function are severely
impaired by hypoxia and adenosine20,21. The transcription
factor hypoxia-inducible factor 1α (HIF1α) is upregulated
by DCs in the hypoxic tumour environment and was
shown to induce the expression of adenosine receptor
A2B by human DCs, causing these DCs to drive the development of TH2 cells (T helper 2 cells) rather than that of TH1
cells, which have more-potent antitumour activity 22. DCs
differentiated in the presence of adenosine had impaired
allostimulatory activity in a mixed leukocyte reaction,
and they expressed higher levels of the pro-angiogenic
cytokine VEGF, the pro-inflammatory cytokines IL‑6
and IL‑8, and the immunosuppressive mediators IL‑10,
cyclooxygenase 2 (COX2), transforming growth factor-β
(TGFβ) and indoleamine 2,3‑dioxygenase (IDO)23.
Addition of lactic acid during DC differentiation
in vitro also induced a phenotype comparable with that
of tumour-associated DCs. Blockade of lactic acid production reverted the tumour-induced DC phenotype
to normal24. DCs found in the peripheral blood and
lymphoid organs of tumour-bearing mice or of patients
with cancer, and especially DCs closely associated with
the tumour, have an increased accumulation of lipids.
This is mediated primarily through upregulation of
macrophage scavenger receptor types I and II, and it
impairs the ability of DCs to process soluble proteins
and stimulate tumour-specific T cell responses25.
Some DCs in tumour-bearing hosts actively suppress
T cell function, and both phenotypically immature and
phenotypically mature DCs may be conditioned by the
environment to support immune tolerance or immuno­
suppression 26,27. MHC-II +CD11b +CD11c + tumourinfiltrating mouse DCs have been shown to suppress
CD8+ T cells and antitumour immune responses through
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Table 1 | Phenotypic definitions used for isolating different myeloid cell populations
Damage-associated
molecular patterns
(DAMPs). As a result of cellular
stress, cellular damage and
non-physiological cell death,
DAMPs are released from the
degraded stroma (in the case
of hyaluronate, for example),
from the nucleus (in the case of
high-mobility group box 1
protein (HMGB1), for example)
and from the cytoplasm (for
example, in the case of ATP,
uric acid, S100 calcium-binding
proteins and heat-shock
proteins). Such host-derived
DAMPs are thought to
promote local inflammatory
reactions.
TH2 cells
(T helper 2 cells). CD4 T cells
are classified on the basis of
the types of effector cytokine
that they secrete. TH2 cells
produce interleukin‑4 (IL‑4),
IL‑5 and IL‑13, and they
support humoral immunity and
downregulate TH1 cell
responses.
+
Tissue
Cell population
Subpopulations
Phenotype
Mouse
lymphoid
organs
DCs
ND
CD11c+F4/80–GR1–MHC-II+
Conventional DCs*
CD11c+CD11b+MHC-II+CD205+F4/80–GR1–CD115low
Plasmacytoid DCs
CD11c+CD11b–B220+SIGLEC-H+GR1+F4/80–
ND
CD11b+LY6C+LY6G–CD11c–CD115+
Resident monocytes
CD11b+LY6ClowLY6G–CD115+MHC-II–F4/80hiCD11c–
Inflammatory monocytes
CD11b+LY6ChiLY6G–CD115+MHC-II–F4/80+CD11c–
ND
F4/80+CD11b+GR1–
M1 macrophages
iNOS+IL‑12+CD86+MHC-IIhi
M2 macrophages
CD206+CD163+CD36+ARG1+MHC-IIlowIL‑10+IL-4Rα+
FIZZ1+YM1+
Granulocytes
Various
CD11b+LY6G+LY6ClowF4/80–CD11c–
MDSCs
ND
CD11b+GR1+CD11c–F4/80+/–CD124+
Polymorphonuclear MDSCs
CD11b+GR1hiLY6ClowLY6G+CD49d–
Monocytic MDSCs
CD11b+GR1midLY6ChiLY6G–CD49d+
ND
LIN–HLA-DR+BDCA1+CD209+
Monocytes
Macrophages
Mouse
tumours
Human
blood
TH1 cells
(T helper 1 cells). TH1 cells
produce interferon‑γ,
lymphotoxin‑α and tumour
necrosis factor, and they
support cell-mediated
immunity. An imbalance
between TH1 cell responses
and TH2 cell responses is
thought to contribute to the
pathogenesis of various
infections, allergic responses
and autoimmune diseases.
Mixed leukocyte reaction
A tissue-culture technique for
testing T cell reactivity and
antigen-presenting cell (APC)
activity. A population of
T cells is cultured with
MHC-mismatched APCs, and
the proliferation of the T cells
is determined by measuring
the incorporation of
3
H-thymidine into the DNA
of dividing cells.
Indoleamine
2,3‑dioxygenase
(IDO). An intracellular
haem-containing enzyme that
catalyses the oxidative
catabolism of tryptophan. IDO
suppresses T cell responses
and promotes immune
tolerance in mammalian
pregnancy, tumour resistance,
chronic infection,
autoimmunity and allergic
inflammation.
Human
tumours
DCs‡
Conventional DCs
LIN–CD11c+CD11b+CD33+BDCA1+BDCA3+DC-SIGN+
Plasmacytoid DCs
LIN–CD123+BDCA2+BDCA4+
Monocytes‡
ND
CD14+HLA-DR+CD15–
Macrophages
ND
CD14+CD68+
M1 macrophages
iNOS+IL‑12+CD86+HLA-DR+
M2 macrophages
CD206+CD163+CD36+HLA-DRlowIL‑10+CD124+
Granulocytes||
ND
CD15+CD14–CD66b+CD16+
MDSCs
ND
LIN–CD11b+HLA-DR–CD33+
Polymorphonuclear MDSCs
In addition to the above MDSC phenotype, these
cells express CD15 and/or CD66b
Monocytic MDSCs
CD33+CD14+HLA-DRlow/–
§
¶
ARG1, arginase 1; BDCA1, blood DC antigen 1 (also known as CD1c); BDCA2, blood DC antigen 2 (also known as CD303); BDCA3,
blood DC antigen 3 (also known as CD141); BDCA4, blood DC antigen 4 (also known as CD304); DC, dendritic cell; DC-SIGN,
DC-specific ICAM3-grabbing non-integrin; IL, interleukin; iNOS, inducible nitric oxide synthase; LIN, lineage markers (a lineage
cocktail of antibodies specific for CD3, CD14, CD19 and CD56 is used to identify other leukocyte populations in the sample);
MHC-II, MHC class II; MDSC, myeloid-derived suppressor cell; ND, not determined; SIGLEC-H, sialic acid-binding
immunoglobulin-like lectin H. *Expression of 33D1 antigen (also known as DCIR2) or of DEC205 (also known as CD205) is specific
for mouse DCs, but these markers are not expressed by all conventional DCs. ‡The mononuclear fraction is separated on a
standard Ficoll gradient. §Expression of DEC205 is specific for human DCs but this marker is not expressed on all conventional DCs.
||
These cells are usually not present in the mononuclear fraction and require sedimentation after the removal of mononuclear cells.
¶
These cells are purified on a standard Ficoll gradient for the isolation of mononuclear cells.
arginase 1 (ARG1) production28, an immuno­suppressive
mechanism previously attributed only to mouse tumourassociated macrophages (TAMs) and MDSCs (see
below). Interestingly, pDCs infiltrating prostate tumours
also use ARG1 and IDO to alter the functions of intratumoural CD8+ T cells, suggesting that immunosuppressive
programmes might be shared across different myeloid
cells in cancer 29. Human lung tumour cells can convert
mature DCs into TGFβ-producing cells30, and mouse
lung cancer can drive DCs to express high levels of IL‑10,
nitric oxide, VEGF and ARG1 (REF. 31).
The accumulation of IDO-expressing DCs (most of
which are pDCs) in tumour-bearing mice and in some
patients with cancer 32,33 provides another possible mechanism of immune suppression, as IDO activity limits T cell
growth by depleting l‑tryptophan and also promotes
T cell apoptosis by generating l‑tryptophan metabolites
and by altering redox potentials through consumption
of superoxide radicals. Evidence supports the hypothesis
that IDO-expressing DCs enhance the suppressive abilities of forkhead box P3 (FOXP3)-expressing regulatory
T cells (TReg cells) in certain settings of chronic inflammation34. As mentioned above, such immunosuppressive
activities are primarily associated with DCs localized in
tumour sites. However, abnormal DC differentiation
and defective DC function is a systemic phenomenon
that affects the myeloid cell lineage during cancer, as
described in more detail below.
Macrophages
Macrophages are a group of terminally differentiated
myeloid cells that are closely related to DCs. They are
tissue-resident cells derived from monocytes circulating in peripheral blood. The macrophage population
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Tumour
TGFβ
PGE2,
COX2,
TGFβ
TH2 cell
TReg cell
IL-4
IL-13
Resulting
TAM
phenotype
IL-10hi
IL-12low
EGF+
IL-10
CD206hi
CD163hi
MHC-IIlow
CCL18+
LPS-nonresponsive
Hypoxia
B cell
TNF,
PGE2
COX2
IL-23
IL-10
YM1+
FIZZ1+
IFNβ+
CCL5+
IL-10low
CD68+
Inflammation
IL-10hi
IL-12low
CD206hi
MHC-IIlow
MMP9+
IL-1β+
CCL5+
CCL22+
MMP7+
CD163+
CCL2,
plasminogen
TIE2+
Tumour-associated
macrophage (TAM)
IL-6+
PDL1+
CD11b+
F4/80+
FIZZ1+
YM1+
CD68+
Recruitment of
macrophages
to the tumour
S100A8,
S100A9
MDSC
IL-10,
TGFβ
IL-12low
CD163+
CD1d+
CD206+
IL-4Rα+
IL-12low
IL-10hi
TGFβ+
Figure 2 | The tumour microenvironment polarizes macrophages towards a tumour-promoting phenotype.
Tumour cells produce factors that drive the generation of multiple types of regulatory immune cells, including T helper 2
(TH2) cells, regulatory T (TReg) cells, B cells and myeloid-derived suppressor cells (MDSCs). Tumour cells also modify their
Reviews | Immunology
local microenvironment to promote hypoxia and inflammation. Cells in the modified tumourNature
microenvironment
subsequently produce cytokines, chemokines and other molecules that promote the development of immunosuppressive
tumour-associated macrophages (TAMs). Local hypoxia promotes macrophage expression of the angiopoietin receptor
TIE2, which downregulates antitumour functions in macrophages. Cytokines produced by regulatory immune cells inhibit
the antitumour response by suppressing macrophage expression of MHC class II molecules and interleukin‑12 (IL‑12), and
by promoting macrophage expression of the anti-inflammatory cytokine IL‑10. Chemokines, such as CC‑chemokine
ligand 2 (CCL2) and CCL5, promote further TAM development by enhancing the recruitment of macrophages to the
tumour site. Factors derived from the tumour itself, such as tumour necrosis factor (TNF) and prostaglandin E2 (PGE2),
also directly polarize macrophages. Crosstalk between tumour cells and MDSCs and between tumour cells and
pro-inflammatory factors in the tumour microenvironment further amplifies the antitumour effects. See the main text for
references and for a more detailed discussion of the molecules and cellular interactions that have been described for
mouse macrophages and for human macrophages in the tumour environment. COX2, cyclooxygenase 2; EGF, epidermal
growth factor; IFNβ, interferon-β; IL‑4Rα, IL‑4 receptor α-chain; LPS, lipopolysaccharide; MMP, matrix metalloproteinase;
PDL1, PD1 ligand 1; TGFβ, transforming growth factor-β.
Regulatory T cells
(TReg cells). A specialized subset
of CD4+ T cells that can
suppress both innate and
adaptive immune responses.
These cells provide a crucial
mechanism for the
maintenance of peripheral
self-tolerance, but may also
limit the effectiveness of
antitumour immune responses.
includes a broad range of cells, the markers and functions of which reflect their tissue microenvironment
(TABLE 1) . Their function in healthy individuals is to
eliminate infectious agents, promote wound healing and
regulate adaptive immunity (reviewed in REF. 35).
The terminology ‘M1 macrophage’ and ‘M2 macrophage’ was coined to describe the different functional states of macrophages and was originally based
on studies of mouse macrophages36. M1 or ‘classically
activated’ macrophages are activated by IFNγ and bacterial products, express high levels of IL‑12 and low levels
of IL‑10, and are tumoricidal. By contrast, M2 or ‘alternatively activated’ macrophages are activated by IL‑4,
IL‑10, IL‑13 and glucocorticoid hormones, express
high levels of IL‑10 and low levels of IL‑12, and facilitate tumour progression. As discussed by Mantovani37,
the M1/M2 nomenclature is useful but is oversimplified
because macrophages form a continuum of phenotypes.
Although there are some differences between M2‑like
mouse and human macrophages, phenotypically and
functionally the macrophages in these two species are
quite similar (TABLE 1).
The role of macrophages in promoting tumorigenesis.
There is extensive literature demonstrating that, in both
mice and humans, macrophages are co-opted during
malignancy to facilitate tumour growth (reviewed in
REFS 1,2,37,38) (FIG. 2). Their presence is associated with
poor clinical outcome1,38, and their pivotal role in cancer was recently highlighted by the demonstration that
TAMs with a specific gene signature are associated with
primary treatment failure in patients with Hodgkin’s
lymphoma39. TAMs are M2‑like macrophages, and
they mediate their effects via both non-immune and
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Plasminogen
Plasminogen is the inactive
precursor of plasmin, a serine
protease involved in the
dissolution of fibrin blood clots.
A causal role has been
suggested for plasmin
generation in cancer cell
invasion through extracellular
matrix remodelling.
Invariant NKT cells
(Invariant natural killer T cells).
A type of lymphocyte thought
to be particularly important in
bridging innate and adaptive
immunity. These cells express a
particular T cell receptor
variable gene segment (Vα14
in mice and Vα24 in humans)
that is precisely linked to a
particular joining (Jα) gene
segment. Typically, NKT cells
co-express cell-surface markers
encoded by the natural killer
locus, and are activated by
recognition of CD1d.
immune mechanisms. Their non-immune mechanisms
include the promotion of angiogenesis40, the facilitation of tumour cell invasion and metastasis41, and the
protection of tumour cells from chemotherapy-induced
apoptosis42 (see also reviews in REFS 1,2,37,38,43).
TAMs sabotage antitumour immunity by eliminating
M1 macrophage-mediated innate immune responses
and by impairing T cell activation. Studies using transgenic mice have showed that IL‑12 produced by M1
macrophages promotes the activation of natural killer
(NK) cells and TH1 cells, which facilitate the activation
of cytotoxic T lymphocytes (CTLs). However, because
TAMs do not produce IL‑12, they do not contribute
to the activation of NK cells and T H1 cells. Instead,
they produce IL‑10 and drive the development of TH2
cells. TH2 cells do not support the development of
CTL responses, and their production of IL‑4 drives
the development of TAMs44. In addition, IL‑10 that is
produced by macrophages in the inflamed intestinal
lamina propria is required to maintain TReg cell activity
and prevent autoimmune colitis45, raising the possibility that TAM-derived IL‑10 may also promote tumour
progression by enhancing TReg cell activity.
TAMs are ineffective antigen-presenting cells,
and they produce CC‑chemokine ligand 22 (CCL22),
which attracts TReg cells that inhibit T cell activation46.
Secretion of prostaglandin E2 (PGE2) and TGFβ 47
by TAMs further contributes to immune suppression.
TAMs can also cause T cell apoptosis through their
expression of PD1 ligand 1 (PDL1), which binds to its
receptor programmed cell death protein 1 (PD1) on
activated T cells48, and mouse macrophages produce
ARG1, which deprives T cells of the l‑arginine that
is necessary for their growth49. A similar mechanism is
also used by MDSCs (see below). Inflammation
is important for the recruitment of macrophages to
tumour sites, and the pro-inflammatory mediators
CCL2 (REF. 50) and plasminogen51,52 have essential roles
in this process.
TAM polarization. Because different areas of solid
tumours have distinct microenvironments, the TAMs
found within an individual tumour vary in phenotype and function. Seven subsets of TAMs have been
identified in mouse mammary carcinoma and lung
adenocarcinoma based on their expression of LY6C,
MHC class II molecules, CX 3C‑chemokine receptor 1 (CX3CR1), CC‑chemokine receptor 2 (CCR2)
and CD62L (also known as L‑selectin). These subsets
have different half-lives, and their relative frequencies change as the tumour microenvironment evolves
with disease progression53. Pro-angiogenic TAMs may
express the angiopoietin receptor TIE2 (REF. 54) and/or
have low expression levels of MHC class II mol­ecules,
and they localize to hypoxic regions 53. TAMs that
promote early tumour cell invasion are enriched for
WNT7B, a protein that is involved in normal developmental and repair responses55. Tumour-derived TGFβ
and PGE2 promote the differentiation of macrophages
that express high levels of GR1 and low levels of markers
associated with M1‑type macrophages47.
T cells have an important role in macrophage regulation during tumorigenesis. In a mouse model of breast
cancer driven by transgenic expression of the polyomavirus middle T antigen, mice with mammary adenocarcinomas developed TH2 cells that produced IL‑4, which
polarized TAMs to an M2 phenotype. These TAMs produced epidermal growth factor (EGF), which initiates
tumour cell invasion, migration and metastasis by signalling through the corresponding receptor on malignant mammary epithelial cells44. TReg cells also regulate
macrophages by orchestrating monocyte differentiation.
A population of human CD4+CD25+CD127lowFOXP3+
TReg cells was shown to induce monocytes to differentiate into M2 macrophages by inhibiting their responsiveness to lipopolysaccharide (LPS), which induces M1
polarization, and by increasing their expression of the
mannose receptor CD206 and the scavenger receptor
CD163. TReg cell production of IL‑10, IL‑4 and IL‑13
promotes the non-responsiveness of macrophages to
LPS56. In contrast to TReg cells, Vα24‑invariant NKT cells
show cytotoxic activity towards TAMs and facilitate
tumour rejection57.
B cells also polarize macrophages towards a tumourpromoting phenotype58. A recent study in a mouse B16
melanoma model has shown that B cells decrease the
production of tumour necrosis factor (TNF), IL‑1β
and CCL3 by macrophages, whereas they increase
macrophage production of IL‑10. This facilitates protumour macrophage activity as well as the synthesis of the M2‑associated markers YM1 (also known
as CHI3L3) and FIZZ1 (also known as RELMα)59. In
another report, autoantibodies polarized leukocytes,
including macrophages, towards a tumour-promoting
phenotype by interacting with activating Fc receptors on
the leukocytes60.
Polarization of macrophages towards an M2 phenotype is also mediated directly by tumour cells. For example, human ovarian cancer cells cause macrophages to
produce increased levels of IL‑10, IL‑1β, CCL5, CCL22,
matrix metalloproteinase 7 (MMP7), MMP9, CD206
and CD163. Tumour cell-derived TNF was partially
responsible for this polarization through its induction
of macrophage scavenger receptor types I and II62.
Granulocytes
Granulocytes are myeloid cells that are characterized
by the presence of cytoplasmic granules and a specific
nuclear morphology. The most abundant type of granulocytes in the body is neutrophils, which are also commonly referred to as polymorphonuclear leukocytes
owing to their polylobed nuclei. Neutrophils possess
a complex machinery to engulf and destroy bacteria.
Neutrophils are not released from the bone marrow
until they reach full maturity, but during inflammation
neutrophil precursors (myelocytes and promyelocytes)
can be released62.
Human tumours can be infiltrated by mature granulocytes, the numbers of which can be independent
prognostic factors for tumour recurrence63–66. Recent
evidence has linked granulocytes, and particularly neutrophils, with tumour angiogenesis and metastasis, and
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has provided initial clues about the immunoregulatory
roles of these cells in cancer. Tumour cells and tumourassociated stromal cells produce neutrophil-attracting
CXC-chemokines and prokineticin 2 (the mammalian
orthologue of BV8)67,68. In the lungs, tumour-derived
granulocyte colony-stimulating factor (G‑CSF) also
mobilizes granulocytes to pre-metastatic niches and
supports subsequent metastasis formation, whereas
prokineticin 2 aids tumour cell migration through
Tumour environment
HSC
Basophil
Aberrant differentiation of myeloid cells in
tumour environment
DC
Eosinsophil
Immature myeloid
progenitor cells
Monocyte
Neutrophil
PMN-MDSC
Antigen-specific
T cell tolerance
and nonspecific
suppression
the activation of prokineticin receptor 1 (REF. 69). It is
likely that granulocytes facilitate the angiogenic switch
by expressing MMP9, which promotes tumour angio­
genesis by inducing VEGF expression in neoplastic
tissue70. Mobilized granulocytes also release elastase,
which then enters endosomal compartments of neoplastic cells and degrades insulin receptor substrate 1
(IRS1). Degradation of IRS1 facilitates interactions
between phosphoinositide 3‑kinase (PI3K) and the
receptor for the mitogen platelet-derived growth factor
(PDGF), thus promoting tumour cell proliferation71.
In contrast to these observations, a recent study
demonstrated that, in mice bearing 4T1 breast tumours,
neutrophils inhibited the formation of tumour meta­
stases through direct antitumour effects mediated by
reactive oxygen species (ROS)72. These new data revisit
the old concept of tumour-cytotoxic neutrophils and
suggest a possible dichotomic polarization of neutrophils. Similarly to macrophages, neutrophils have been
shown to shift from an antitumoural ‘N1’ phenotype
to a pro-tumoural ‘N2’ phenotype in the cancer environment 73. TGFβ drives the N2 phe­notype, and TGFβ
blockade promotes an N1 phenotype with antitumour
activity. In lung adenocarcinoma and mesothelioma
models, TGFβ induces tumour-infiltrating neutrophils to develop a pro-tumoural phenotype, which
is characterized by ARG1 expression and low levels
of TNF, CCL3 and intercellular adhesion molecule 1
(ICAM1). In tumour-bearing animals, depletion
of N2 neutrophils led to an increase in CD8+ T cell
activity 73. In line with these findings, serum amyloid
A1 protein induced the expansion of IL‑10‑secreting
neutrophil populations that were able to suppress
the antigen-specific proliferation of CD8+ T cells in
human melanomas74. However, IL‑10 production by
activated human neutrophils was not confirmed in a
subsequent study 75.
Myeloid cells as a single integrated system
Neoplastic cells condition distant sites, such as the
bone marrow and spleen, by releasing soluble factors
that drive the accumulation of myeloid cells; these
myeloid cells subsequently promote neovasculariza• Non-specific suppression
tion and metastasis. This creates a tumour-driven
• Produce cytokines and
‘macro­environment’. As discussed above, this macro­
soluble factors that support
environment conditions DCs, macrophages and
tumour angiogenesis
Suppressive DC
TAM
granulo­cytes to become immunosuppressive. However,
the most prominent effect is the accumulation of highly
immunosuppressive, immature myeloid cells. These
cells were named MDSCs to highlight their comFigure 3 | Changes that occur in myeloid cells in cancer. Factors produced in the
mon myeloid origin and immunoregulatory proper76
tumour microenvironment by tumour cells and stromal cellsNature
promote
the aberrant
Reviews
| Immunology ties (TABLE 1). Immature myeloid cells with the same
differentiation of myeloid lineage cells. The dotted lines show the normal pathways
pheno­type as MDSCs are continually generated in the
of myeloid cell differentiation from immature myeloid precursor cells to dendritic
bone marrow of healthy individuals and differentiate
cells (DCs), macrophages and granulocytes, as depicted in FIG. 1. The solid bold lines
into mature myeloid cells without causing detectable
indicate the aberrant pathways of myeloid cell differentiation that occur in cancer,
immunosuppression. However, in cancer, myeloid cell
in which the tumour environment can promote the development of various
differentiation is diverted from its normal pathway —
immunosuppressive populations, including monocytic myeloid-derived suppressor
cells (M-MDSCs), polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which leads to the terminal differentiation of mature
macrophages, DCs and granulocytes — towards a
suppressive DCs and tumour-associated macrophages (TAMs). The dotted thick line
pathway that favours the differentiation of pathological
depicts a pathway of cell differentiation that has been suggested but has not yet been
MDSCs (FIG. 3).
confirmed. HSC, haematopoietic stem cell.
Macrophage
M-MDSC
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Characteristics of MDSCs. MDSCs were originally identified in tumour-bearing mice as cells that co-express
CD11b and GR1; however, their phenotype in cancer is
rather diverse77,78. Currently, two main MDSC populations have been characterized: monocytic MDSCs and
polymorphonuclear MDSCs (also known as granulocytic
MDSCs) (TABLE 1).
In tumour-bearing mice, the polymorphonuclear
MDSC subset is the prevalent population of MDSCs.
Polymorphonuclear MDSCs suppress antigenspecific CD8+ T cells predominantly by producing ROS.
Polymorphonuclear MDSCs represent the major subset
of circulating MDSCs; however, they are less immuno­
suppressive than monocytic MDSCs when assessed
on a per cell basis79–81. In human studies, the number
of monocytic MDSCs, but not of polymorphonuclear
MDSCs, correlated directly with suppression of in vitro
T cell activation82.
In addition to their specific markers (TABLE 1), monocytic MDSCs express varying levels of classic monocyte
markers, such as F4/80 (also known as EMR1), CD115
(also known as M‑CSFR), 7/4 (also known as LY6B)
and CCR2 (REFS 79–81,83). They suppress CD8+ T cells
predominantly via expression of the enzymes ARG1 and
inducible nitric oxide synthase (iNOS) and through the
production of reactive nitrogen species79–81. This subset
of MDSCs may also include progenitors that give rise
to a subset of CD11bhiGR1lowLY6G–F4/80hiMHC-II+
macrophages with potent immunosuppressive
properties81,84–86.
MDSCs with the phenotype LIN – HLA-DR –
CD33+CD11b+ have been isolated from the blood of
patients with glioblastoma, breast cancer, colon cancer,
lung cancer or kidney cancer 78,87–90. These cells share
features and properties with progranulocytes89. The
frequency of this immature cell population may reflect
the tumour burden, and a high frequency correlates
with a poor prognosis and radiographic progression
in patients with breast or colorectal cancer 88,89,91. In
addition, the frequency of each MDSC subset appears
to be influenced by the type of cancer. Patients with
renal cancer have immunosuppressive CD11b+CD14–
CD15+CD66b+VEGFR1+ polymorphonuclear MDSCs92,
whereas CD14+CD11b+HLA-DRlow/– monocytic MDSCs
circulate in the blood of patients with melanoma, multiple myeloma, prostate cancer, hepatocellular carcinoma
or head and neck cancer 82,93–96.
Relationship of MDSCs to other myeloid cells. Despite
their morphological similarity, polymorphonuclear
MDSCs and neutrophils are functionally and phenotypically different. First, polymorphonuclear MDSCs,
but not neutrophils, are immunosuppressive97. Second,
polymorphonuclear MDSCs express higher levels of
CD115 and CD244 than neutrophils but lower levels
of CXC‑chemokine receptor 1 (CXCR1) and CXCR2
(REFS 97,98). Finally, compared with neutrophils, polymorphonuclear MDSCs are less phagocytic, express
higher levels of ARG1 and myeloperoxidase, have
increased ROS production and show reduced chemotaxis
towards supernatants from human carcinomas97,98.
Similarly, although monocytic MDSCs and inflammatory monocytes share a common phenotype and
morphology, these cell populations are functionally distinct. Monocytic MDSCs are highly immunosuppressive,
as they express, among other factors, high levels of both
iNOS and ARG1. By contrast, iNOS and ARG1 are not
coordinately upregulated in monocytes. Furthermore,
although in M1 macrophages iNOS expression is a hallmark of a tumoricidal phenotype, in monocytic MDSCs
iNOS expression promotes suppressive activities36. This
shift in iNOS activity probably reflects the interplay of
iNOS with other enzymes expressed by MDSCs, such as
ARG1 and NADPH oxidase, as the coordinated activity
of these enzymes was shown to promote the production
of peroxynitrite, which inhibits the proliferation, effector
functions and migration of T cells99–102. Although differences exist in the expression of ARG1 and iNOS among
mouse and human myeloid cells (for example, ARG1 is
constitutively expressed by human granulocytes103 but
not monocytes), evidence indicates that human MDSCs
can also co-express these enzymes96,104.
The MDSC population includes direct progenitors
of DCs, macrophages and granulocytes. After 24 hours of
in vitro culture, polymorphonuclear MDSCs phenotypically and functionally resemble neutrophils97. Culture of
tumour-derived MDSCs in the absence of tumour-derived
factors, or the transfer of MDSCs to tumour-free recipients, results in the generation of mature macrophages and
DCs105–107. By contrast, the presence of tumour-derived soluble factors or adoptive transfer into tumour-bearing hosts
promotes the differentiation of MDSCs into immuno­
suppressive macrophages107,108. MDSCs can also differentiate into DCs following transfer into tumour-bearing
recipients109, but whether these DCs are immunosuppressive is not currently known. Furthermore, hypoxia in the
tumour microenvironment drives the differentiation of
MDSCs into TAMs109,110 (FIG. 3).
Immunomodulatory functions of MDSCs. MDSCs
exploit a plethora of redundant mechanisms to influence both innate and adaptive immune responses (FIG. 4).
Broadly speaking, these mechanisms can be grouped
into four classes. The first type of mechanism is the
depletion of nutrients required by lymphocytes — specifically, l‑arginine depletion through ARG1‑dependent
consumption49 and l‑cysteine deprivation via its consumption and sequestration111. The depletion of these
amino acids causes downregulation of the ζ‑chain in the
T cell receptor (TCR) complex and proliferative arrest
of antigen-activated T cells.
The second type of mechanism is the generation
of oxidative stress, which is caused by the production of ROS and reactive nitrogen species by MDSCs.
Peroxynitrite and hydrogen peroxide are produced by
the combined and cooperative activities of NADPH oxidase, ARG1 and iNOS in different MDSC subsets, and
these reactive species drive several molecular blocks in
T cells, ranging from the loss of TCR ζ‑chain expression112 and interference with IL‑2 receptor signalling 113
to the nitration and subsequent desensitization of
the TCR101.
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Natural TReg cells
A subset of TReg cells that
undergoes maturation in the
thymus, where these cells
acquire the ability to recognize
with intermediate avidity self
antigens presented by host
MHC class II molecules before
being released to the
periphery.
Induced TReg cells
A subset of TReg cells that is
derived from the direct
conversion of CD4+ naive
T cells in peripheral lymphoid
organs in several situations,
including the interaction
with tumour-conditioned
myelomonocytic cells in
tumour-bearing hosts.
TH17 cell
(T helper 17 cell). A CD4+
T helper cell that produces
IL‑17 and that is thought to
be important in mediating
host defence against certain
infections, particularly at
mucosal tissues. These cells
are also thought to drive
pathology in certain
inflammatory and autoimmune
diseases, such as Crohn’s
disease.
The third type of mechanism interferes with
lymphocyte trafficking and viability. Expression of
ADAM17 (disintegrin and metalloproteinase domaincontaining protein 17) at the plasma membrane of
MDSCs decreases CD62L expression on the surface
of naive CD4+ and CD8+ T cells, thereby limiting T cell
recirculation to lymph nodes114. Another example is the
modification of CCL2 by MDSC-derived peroxynitrite,
a process that impairs the migration of effector CD8+
T cells to the tumour core102. Furthermore, MDSCs
express galectin 9, which binds to T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on
lymphocytes and induces T cell apoptosis115. MDSCs
also decrease the number and inhibit the function of
mouse and human NK cells, mostly through membrane contact-dependent mechanisms (that is, through
membrane-bound TGFβ (in the case of mouse MDSCs)
and through interaction with the NK cell receptor
NKp30 (also known as NCR3))116–118.
The fourth type of mechanism is the activation
and expansion of TReg cell populations. MDSCs promote the clonal expansion of antigen-specific natural
TReg cells and also induce the conversion of naive CD4+
T cells into induced TReg cells. The mechanisms are not
completely understood, but may involve cell-to-cell
contact (including CD40–CD40L interactions)119, the
production of soluble factors (such as IFNγ, IL‑10 and
TGFβ) by MDSCs120 and possibly also the expression of
ARG1 by MDSCs121 (FIG. 4). Human CD14+HLA-DRlow/–
MDSCs promote the transdifferentiation of TH17 cells
into FOXP3+ induced TReg cells by producing TGFβ and
retinoic acid122.
In peripheral lymphoid organs, MDSC-mediated
suppression of CD8+ T cells is usually antigen specific
and requires the presentation of antigens by MDSCs and
direct MDSC–T cell contact 101,123. By contrast, in the
periphery 124 and at the tumour site109,110,125,126, the activity of MDSCs is enhanced by activated T cells, and as
a result MDSCs are able to suppress nearby T cells in
an antigen-nonspecific manner. However, if T cells are
activated and begin to express FAS ligand (also known
as CD95L), they may induce the apoptosis of FAS +
MDSCs124.
The co-dependence of cells in the myeloid lineage
is further demonstrated by the regulation of mature
DCs and macrophages by MDSCs. Through an IL‑10and cell contact-dependent mechanism, MDSCs
skew macrophages towards an M2 phenotype by
decreasing macrophage production of IL‑12 (REF. 127).
The downregulation of IL‑12 is exacerbated by the
macrophages themselves, as macrophages promote
the production of IL‑10 by MDSCs (FIG. 4). As MDSC
potency is increased by inflammation 128, it is not
unexpected that inflammation enhances the crosstalk
between MDSCs and macrophages. Inflammation
mediates these effects by upregulating the expression of
CD14 and increasing signalling through the TLR4 pathway in MDSCs129. MDSCs similarly impair DC function by producing IL‑10, which inhibits TLR-induced
IL‑12 production by DCs and reduces DC‑mediated
activation of T cells130.
Mechanisms of tumour impact on myeloid cells
Neoplastic cells and tumour-associated stromal cells
release multiple tumour-derived soluble factors that
perturb the myeloid compartment. Cytokines such
as granulocyte–macrophage colony-stimulating factor (GM‑CSF), G‑CSF, M‑CSF, stem cell factor (SCF;
also known as KIT ligand), VEGF and IL‑3 promote
myelopoiesis and contribute, in part, to a blockade of
myeloid cell maturation86,105 (FIG. 5). Tumour-derived
soluble factors that are pro-inflammatory (such as IL‑1β,
IL‑6, S100A8 and S100A9)131–133, as well as cytokines
released by activated T cells (such as IFNγ, IL‑4, IL‑10
and IL‑13)125, initiate the immunosuppressive pathways that commit immature myeloid cells to become
MDSCs and then further promote the differentiation
of MDSCs towards immunosuppressive macrophages and
DCs (FIG. 5). The tumour-derived factors CCL2, CCL12,
CXC‑chemokine ligand 5 (CXCL5), pro­kineticin 2,
S100A8 and S100A9 recruit immature myeloid cells to
the tumour stroma68,134,135. Immature myeloid cells are
also attracted by CCL2 that is nitrated or nitrosylated
in the tumour environment. By contrast, effector CD8+
T cells are not recruited by modified CCL2, which may
explain the selective enrichment of myelomonocytic cells
within mouse and human tumours102.
LPS, in combination with IFNγ, promotes the expansion of MDSC populations, probably by inhibiting DC
differentiation136. Tumour-derived TGFβ also regulates
MDSC accumulation137 and neutrophil polarization73
(FIG. 5). Neoplastic cells and their associated stromal
cells also release into the bloodstream subcellular components known as exosomes, which contain signal
peptides, mRNAs, microRNAs and lipids and promote
MDSC population expansion (reviewed in REF. 138).
Tumour-derived soluble factors regulate myeloid
lineage cells on multiple levels through a variety of trans­
cription factors86,105,128 (FIG. 5), with signal transducer and
activator of transcription 3 (STAT3) playing a major role.
Early studies identified STAT3 as a crucial regulator of
DC and macrophage defects139,140 and MDSC population expansion141–143. STAT3 not only prevents apoptosis
and promotes cell proliferation by upregulating the antiapoptotic or pro-proliferative factors B cell lymphoma XL
(BCL-XL), MYC, cyclin D1 and survivin105,144, but also
regulates the expression of multiple proteins that are
crucial for the differentiation of myeloid cells. One such
pathway involves the calcium-binding pro-inflammatory
proteins S100A8 and S100A9 (REF. 145). STAT3‑mediated
upregulation of these proteins in myeloid progenitors
inhibits DC differentiation and promotes MDSC accumulation146. S100A8 and S100A9 also enhance the suppressive activity of MDSCs and recruit MDSCs to the tumour
site132. Myeloid cell NADPH oxidase is another important
target of STAT3. STAT3‑mediated upregulation of the
NADPH oxidase components p47phox (also known as
NCF1) and gp91phox (also known as CYBB) increases
ROS levels, thereby making MDSCs more suppressive90.
STAT3 also downregulates protein kinase Cβ isoform II
(PKCβII), which is required for DC differentiation, and
thus prevents the development of DCs into mature cells147.
In addition, STAT3 regulates the transcription factor
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a
b
T cell
TReg cell
IL-10
TGFβ
↓ L-arginine
L-cystine
↑ FOXP3
CD40L
↓ L-arginine
Altered mRNA
transcription
CAT2B
• Loss of TCRζ chain
• Proliferative arrest
PI3K
mTOR
T cell
L-arginine
Cell cycle
RAGE
S100A8
S100A9
Loss of TCRζ chain
H2O
T cell
ARG1
L-cysteine
c
H2O2
ARG1
ASC
L-cystine
MDSC
HuR
EIF2A
↓ L-cysteine
MHC
class II
CD40
TCR
GCN2
L-arginine
Xc–
TCR
Chemotaxis S100A8
S100A9
Cyclin D3
mRNA instability
Proliferative
arrest
T cell
NOX
iNOS
O2–
NO
STAT3
STAT6
STAT1
C/EBPβ
HIF1α
MYD88
↓ L-arginine
d
TGFβ
NK cell
ADAM17
CD62L
Naive
T cell
IL-10
ONOO–
Inhibition
of NK cells
CD8
GAL9
TIM3
Nitration or
nitrosylation
of TCR, CD8
and CD3
Nitrosylation
↑ cGMP
PI3K–AKT
STAT5
ERK2
Nitration or
nitrosylation
of CCL2
CD3
TCR
CD8
Apoptotic
T cell
TCR
CD8
CD3
CCR2
Apoptosis
IL-2R
T cell
IL-2
Effector
T cell
↑ IL-10
↓ IL-12
T cell
T cell
Macrophage
Decreased
effector T cell
activation
Inhibition
of T cell
recruitment
Figure 4 | Mechanisms of MDSC-dependent inhibition of T cell activation and proliferation. Myeloid-derived
suppressor cells (MDSCs) can inhibit efficient antitumour T cell responses through a number ofNature
mechanisms.
Reviews | Immunology
a | Tumour-associated MDSCs induce the development of regulatory T (TReg) cells or expand existing TReg cell populations.
The calcium-binding proteins S100A8 and S100A9 are involved in the chemotaxis of MDSCs and other myeloid cells; these
effects are mediated in part through the activation of receptor for advanced glycation end-products (RAGE). At the same
time, S100A8 and S100A9 along with gp91phox are part of the NADPH oxidase (NOX) complex that is responsible for the
increased production of reactive oxygen species (ROS) by MDSCs. b | Tumour-associated myeloid cells deprive T cells of
amino acids that are essential for their growth and differentiation. c | Tumour-associated myeloid cells release oxidizing
molecules, such as hydrogen peroxide (H2O2) and peroxynitrite (ONOO–). Peroxynitrite causes nitration and nitrosylation of
components of the T cell receptor (TCR) signalling complex, and H2O2 causes the loss of the TCR ζ‑chain, thereby inhibiting
T cell activation through the TCR. d | Tumour-associated myeloid cells can also interfere with T cell migration and viability.
The metalloproteinase ADAM17 (disintegrin and metalloproteinase domain-containing protein 17) cleaves CD62L, which is
necessary for T cell migration to draining lymph nodes, and galectin 9 (GAL9) can engage T cell immunoglobulin and mucin
domain-containing protein 3 (TIM3) on T cells to induce apoptosis. As the induction of the immunosuppressive pathways
that are depicted in the figure is regulated by common transcription factors, these pathways can operate in more than one
myeloid cell type (see FIG. 5). ARG1, arginase 1; ASC, asc-type amino acid transporter; CAT2B, cationic amino acid
transporter 2 isoform 1 (l-arginine transporter); CCL2, CC‑chemokine ligand 2; CCR2, CC‑chemokine receptor 2; C/EBPβ,
CCAAT/enhancer-binding protein-β; EIF2A, eukaryotic translation initiation factor 2A; ERK2, extracellular signal-regulated
kinase 2; FOXP3, forkhead box P3; HIF1α, hypoxia-inducible factor 1α; HuR, Hu-antigen R (also known as ELAVL1); IL,
interleukin; IL‑2R, IL‑2 receptor; iNOS, inducible nitric oxide synthase; mTOR, mammalian target of rapamycin; MYD88,
myeloid differentiation primary-response protein 88; NK, natural killer; PI3K, phosphoinositide 3‑kinase; STAT, signal
transducer and activator of transcription; TGFβ, transforming growth factor‑β; Xc–, cystine–glutamate transporter.
NATURE REVIEWS | IMMUNOLOGY
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Tumour
microenvironment
Cytokine
or immune
mediator
Transcription
factor
IL-1β, IFNγ
IL-1β, IL-6, IL-10,
IL-11, G-CSF, GM-CSF,
VEGF, HSP70
GM-CSF
IL-4, IL-13
TLR ligands
TGFβ
STAT1
STAT3
STAT5
STAT6
NF-κB
SMADs
S100A8, S100A9, NOX2,
BCL-XL, cyclin D1, survivin,
MYC, C/EBPβ, PKCβII
BCL-XL, cyclins,
survivin, MYC
ARG1; NOX2
and antioxidants
regulating ROS
PGE2; NOX2 and
antioxidants
regulating ROS
Targets of
iNOS, ARG1
transcription
Relevant
myeloid
cells
MDSC
MDSC TAM Suppressive DC
TAM
Immune suppression
mediated by NO and ARG1
Population
expansion;
immune
suppression
mediated by
ROS
MDSC
MDSC TAM
Population
expansion
M2-type
polarization;
immune
suppression
Blockade of
DC activation;
immune
suppression
Immune
M2-type
suppression polarization;
immune
suppression
MDSC
TAM
Neutrophil
Neutrophil
Mobilization Mobilization
from bone
from bone
marrow;
Polarization of
immune
neutrophils to
suppression
a pro-tumour
phenotype
Figure 5 | Molecular mechanisms affecting the myeloid lineage in cancer. The tumour microenvironment
secretes many different cytokines and immune mediators that affect myeloid progenitors as well as mature myeloid
| Immunology
cells by regulating the activity of multiple transcription factors. These transcription factors,Nature
in turn,Reviews
regulate
the
synthesis of their protein targets, thereby affecting myeloid cell functions. ARG1, arginase 1; BCL-XL, B cell
lymphoma XL; C/EBPβ, CCAAT/enhancer-binding protein-β; DC, dendritic cell; G-CSF, granulocyte colony-stimulating
factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; HSP70, heat-shock protein 70; IFNγ, interferon-γ;
IL, interleukin; iNOS, inducible nitric oxide synthase; MDSC, myeloid-derived suppressor cell; NF-κB, nuclear
factor‑κB; NO, nitric oxide; NOX2, NADPH oxidase 2; PGE2, prostaglandin E2; PKCβII, protein kinase Cβ isoform II;
ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TAM, tumour-associated
macrophage; TGFβ, transforming growth factor‑β; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor.
CCAAT/enhancer-binding protein-β (C/EBPβ). C/EBPβ
regulates myelopoiesis in healthy individuals148 and has a
crucial role in controlling the differentiation of myeloid
progenitors to functional MDSCs131. STAT3 is responsible, at least in part, for inducing the expansion of MDSC
populations via upregulation of C/EBPβ and also has an
indirect role in myeloid cell mobilization, accumulation
and survival149.
The transcription factor STAT1 regulates subsets
of myeloid cells through its effects on iNOS expression
and is crucial for immune suppression by macro­
phages and MDSCs81,108,125. Other characteristics of
MDSCs and macrophages (including upregulated
expression of ARG1 (REFS 150–152) and increased TGFβ
production121,153), and possibly the expansion of MDSC
populations154, are controlled by STAT6. IL‑4‑induced
polarization of TAMs activates STAT6, which binds
to the promoter of the gene encoding the demethylase
jumonji domain-containing protein 3 (JMJD3; also
known as KDM6B). Activated JMJD3 demethylates
histone H3 lysine 27 at specific genetic loci, and this
increases the expression of ARG1, YM1 and FIZZ1,
resulting in M2 polarization155. However, the genetic
ablation of Jmjd3 in mice causes a defect in interferonregulatory factor 4 (IRF4)-dependent M2 polarization
in response to M‑CSF, helminth infection or chitin
administration, but not following IL‑4 stimulation,
suggesting a more complex regulatory network156.
The TLR family also has a prominent role in
myeloid cell development, primarily via the activation
of myeloid differentiation primary-response protein 88
(MYD88) and the downstream induction of nuclear
factor‑κB (NF‑κB). NF‑κB signalling is important for the
mobilization of myeloid cells to sites of infection, injury
or tumour growth157,158. TLR4 regulates the inflammation-driven suppressive potency of MDSCs through an
NF‑κB-dependent mechanism129. The pro-inflammatory
mediators COX2 and PGE2, which enhance MDSC
accumulation and suppressive activity 137,159–161, are also
potential targets for NF‑κB162.
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Autochthonous tumour
Differently from transplanted
tumours, which arise from the
experimental transfer of
neoplastic cells or tissues,
autochthonous tumours
develop spontaneously in the
host. Autochthonous tumours
can be derived from either
chemical carcinogenesis or
targeted tissue expression of
oncogenes by genetic
manipulation of mice.
Model of MDSC involvement in tumour progression
Recent studies of autochthonous tumour formation in
transgenic mice indicate that cells with an MDSC phenotype probably intervene in the very early stages of cancer
progression. Mice with autochthonous pancreatic cancer undergo progressive waves of myeloid cell recruitment after the initiation of the transforming programme
driven by the Kras oncogene163. Recruited myeloid cells
contribute to the local production of IL‑6 and IL‑11,
which activate STAT3. STAT3, in turn, induces antiapoptotic and pro-proliferative genes, fuelling tumour
initiation, promotion and progression164,165.
During the early events of colitis-associated cancer,
myeloid cells act as tumour promoters by enhancing the
proliferation of tumour-initiating cells and by protecting
premalignant intestinal epithelial cells from apoptosis166.
In thyroid carcinomas, the oncogenic fusion protein
RET/PTC3 directly induces the production of CCL2
and GM‑CSF, which together promote the recruitment
of CD11b+GR1+ myeloid cells that can promote tumour
progression167,168.
An important question is whether these early recruited
cells are immunosuppressive MDSCs. Unfortunately, only
a few studies in autochthonous tumour models have determined the immunosuppressive activity of the tumourassociated CD11b+GR1+ cells. In models of spontaneous
breast, pancreatic or lung cancer, accumulated myeloid
cells had both the phenotype and immunosuppressive
features of MDSCs109,163,169. Moreover, in a recent study,
conditional deletion of the gene encoding p120 catenin
(a protein involved in cell–cell adhesion and signal transduction) in mice caused the formation of invasive squamous cell cancer and desmoplasia and the associated
production of CCL2, GM‑CSF, M‑CSF and TNF. These
events resulted in the accumulation of immuno­suppressive
CD11b+GR1+CD124+ MDSCs that promoted tumour
progression by activating stromal fibroblasts170.
In another model of multistep squamous carcino­
genesis driven by the human papillomavirus 16 (HPV‑16)
early-region genes (including the E6 and E7 oncogenes)
under the control of the human keratin 14 promoter and
enhancer, CD11b+GR1+F4/80–CD11c– MDSCs were the
most abundant leukocyte subtype in premalignant skin,
and they also accumulated progressively in the spleen.
However, these cells failed to inhibit the polyclonal
activation of either CD4+ or CD8+ T cells and did not
produce ROS60.
These results, together with the data discussed
above from transplantable tumour models, support a
two-stage model of MDSC involvement in cancer. An
almost universal feature of tumour progression is the
activation of abnormal myelopoiesis and the recruitment of immature myeloid cells into tissues. This
process is governed by diverse soluble factors and is
dependent on the upregulation of STAT3 and other key
transcription factors (FIG. 5).
Myelopoiesis during acute infection, stress or trauma
results in rapid terminal differentiation of myeloid cells.
By contrast, cancer myelopoiesis is associated with
defective myeloid cell differentiation, which results in
the accumulation and persistence of immature myeloid
cells. Although necessary, these events are not sufficient to
generate immunosuppressive MDSCs: activation of the
immature myeloid cells via a network of regulatory mechanisms is also required (FIG. 5). The activation of these
mechanisms in mice with most transplantable tumours
and many, but not all, spontaneous tumours results in the
accumulation of immunosuppressive MDSCs. In tumour
sites, these cells further differentiate into TAMs and possibly into suppressive DCs. In patients with cancer, cells
with an MDSC phenotype are almost universally immuno­
suppressive, which may reflect their isolation from patients
with advanced disease. If immuno­suppressive activity
is not a property of the first wave of immature myeloid
cells recruited to tumours, continuous stimulation of
myelopoiesis and activation of immature myeloid cells by
tumour-derived soluble factors may drive the subsequent
accumulation of immunosuppressive MDSCs that support tumour promotion and form the metastatic niche.
Accordingly, the oncogenic programme may have a greater
influence on the functional immunosuppressive activities
of MDSCs than on their accumulation.
The transition from immature myeloid cell to MDSC
might be defective in some experimental tumour models, and different oncogenic programmes may differentially affect the kinetics of immature myeloid cell to
MDSC conversion. Treatment in vitro with combinations of GM‑CSF, G‑CSF, IL‑6 and IL‑13 induces the
rapid differentiation of human and mouse bone marrow
precursor cells into cells that resemble MDSCs89,131,137,171.
These studies may provide the framework for identifying
the key molecules that govern MDSC maturation.
Therapeutic targeting of myeloid cells
It is increasingly clear that successful cancer immunotherapy will require limiting the immunosuppressive effects of
populations of myeloid cells. Knowledge of the molecular
mechanisms responsible for the accumulation of MDSCs
and immunosuppressive macrophages and DCs in cancer
has allowed for therapeutic targeting of these cells. This
targeting is focused on six main goals. The first goal is to
inhibit the molecular mechanisms used by myeloid cells
to block lymphocyte reactivity and proliferation. Second,
targeting should inhibit the generation of MDSCs from
bone marrow progenitors or induce the apoptosis of circulating MDSCs. Third, it should force MDSCs to mature
into proficient APCs that can stimulate tumour-specific
T cells. Fourth, it should prevent the trafficking of myeloid
cells from the bone marrow to peripheral lymphoid organs
and to tumours. The fifth goal is to repolarize or eliminate TAMs and replace them with pro-inflammatory M1
macrophages that enhance antitumour immune responses.
Finally, the sixth goal is to restore the antigen-presenting
capabilities of DCs and macrophages, allowing these
populations to activate effector T cell responses (TABLE 2).
The proposed two-stage model for MDSC involvement might have implications for the further development of therapies. Some immunosuppressive
mechanisms are common to all myeloid cells, but others
are unique to individual populations. Therefore, targeting
common effector molecules is likely to be more effective
than targeting individual suppressive pathways.
NATURE REVIEWS | IMMUNOLOGY
VOLUME 12 | APRIL 2012 | 263
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
Table 2 | Pharmacological regulation of myeloid cells in cancer
Therapeutic treatment
Type of cancer*
Molecular events
Effects on myeloid cells
Refs
Nitroaspirin
Colon carcinoma
Downregulation of ARG1, iNOS and
peroxynitrite in MDSCs
Inhibition of MDSC suppressive effects
172
Phosphodiesterase‑5
inhibitors (sildenafil and
tadalafil)
Mammary carcinoma,
colon carcinoma and
fibrosarcoma
Downregulation of ARG1, iNOS,
and CD124 (IL-4Rα) in MDSCs
Inhibition of MDSC suppressive effects
96
AT38 (an NO donor based
on the furoxan molecule)
Fibrosarcoma and
thymoma
Downregulation of ARG1, iNOS and
peroxynitrite in MDSCs; expression
of nitrated or nitrosylated CCL2
Inhibition of MDSC suppressive effects;
increased CD8+ T cell/MDSC ratio in
tumours
102
Triterpenoids
Colon carcinoma, lung
carcinoma and thymoma
Inhibition of ROS production by
MDSCs
Inhibition of MDSC suppressive effects
173
Tyrosine kinase inhibitor
(sunitinib)
Fibrosarcoma and colon,
breast, lung and kidney
cancer; human renal cell
carcinoma
Possible KIT blockade; STAT3
inhibition; GM‑CSF confers
resistance by activating STAT5 in
intratumoural MDSCs
Inhibition of MDSC expansion in lymphoid
organs but not in the tumour stroma;
modest inhibition of MDSC population
expansion in patients
174–178
Cyclooxygenase 2
inhibitors (SC58236,
SC58125 and celecoxib)
Mammary carcinoma,
mesothelioma, lung
carcinoma and glioma
Downregulation of PGE2, ARG1,
ROS and CCL2 and increase in the
expression of CXCL10 by MDSCs
Inhibition of MDSC suppressive effects
137,162,
179
KIT-specific antibody
Colon carcinoma
Blockade of the KIT–SCF interaction Inhibition of MDSC population expansion
180
CSF1R and KIT receptor
tyrosine kinase inhibitor
(PLX3397)
Mammary carcinoma
Blockade of CSF1R and KIT
181
CCL2-specific
monoclonal antibody
Mammary carcinoma
Interference with CCL2 binding to
Inhibition of metastatic spread by
CCR2 and with VEGFA upregulation targeting inflammatory monocytes and
macrophages
Amino-bisphosphonate
(zoledronate)
Mammary tumours and
mesothelioma
Reduction in VEGF and pro-MMP9
serum levels
Inhibition of MDSC population expansion
Very small size
proteoliposomes
Lymphomas and sarcoma
iNOS downregulation
Changes in MDSC subset distribution
184
Antagonists of CXCR2
(S‑265610) and CXCR4
(AMD3100)
Breast cancer
Interference with the chemokines
CXCL12 and CXCL5
Altered recruitment of immature myeloid
cells to the tumour
134
Prokineticin 2-specific
antibody
Various human and
mouse tumours in nude
mice
Interference with prokineticin 2
pleiotropic activity
Inhibition of polymorphonuclear MDSC
population expansion and recruitment to
tumour and pre-metastatic niches
68,69
CSF1R antagonist
(GW2580)
Lung carcinoma and
prostate cancer
CSF1R interference; downregulation
of ARG1 in MDSCs; reduction in
VEGF and MMP9 levels in the tumour
Inhibition of the expansion of MDSC
and macrophage populations and their
recruitment to the tumour
185
VEGF-Trap (aflibercept),
VEGF-specific antibody
(bevacizumab (Avastin;
Genentech/Roche))
Various human solid
tumours and human
metastatic renal cell
cancer
VEGF interference blocks tumour
growth
Increased functional maturation of DCs
186,187
Gemcitabine
Lung cancer and breast
cancer
MDSC apoptosis
Inhibition of MDSC population expansion
127,188
5-fluorouracil
Thymoma
MDSC apoptosis
Inhibition of MDSC population expansion
189
Doxorubicin–
cyclophosphamide
Human breast cancer
May induce MDSC apoptosis
Weak inhibition of MDSC population
expansion
Docetaxel
Mammary carcinoma
MDSC apoptosis; differentiation of
surviving cells to M1 macrophages
Inhibition of MDSC population expansion;
macrophage polarization to M1 phenotype
All-trans retinoic acid
Sarcoma and colon
carcinioma; human
metastatic renal cell
carcinoma
Differentiation of immature myeloid Inhibition of MDSC accumulation
cells to mature leukocytes
Vitamin D3
Human head and neck
cancer
Forced differentiation of CD34+
immature myeloid cells
Moderate inhibition of MDSC population
expansion
Combined treatment
with IL‑12, CCL16,
CpG DNA and an
IL‑10 receptor-specific
monoclonal antibody
Lung cancer and breast
cancer
Decreased levels of IL‑10, CCL2 and
TGFβ; increased levels of TNF, IL‑15
and IL‑18.
TAM reprogramming
Inhibition of TAM recruitment
264 | APRIL 2012 | VOLUME 12
50
182,183
88
190
191,192
193
194,195
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© 2012 Macmillan Publishers Limited. All rights reserved
F O C U S O N t u m our i m m uno lo g y & i m m unotRh
py
E er
V I EaW
S
Table 2 (cont.) | Pharmacological regulation of myeloid cells in cancer
Therapeutic treatment
Type of cancer*
Molecular events
Effects on myeloid cells
Tumour-specific CTLs
engineered to release
IL‑12; chimeric antigen
receptor-expressing T cells
engineered to release
IL‑12
Melanoma and colon
carcinoma
Increased antigen
cross-presentation and
co-stimulation; acute
inflammation signature (including
IFNγ production); increased TNF
production
DC, MDSC and TAM reprogramming
CD40-specific monoclonal
antibodies plus IL‑2
Renal cell carcinoma
Increased iNOS and TIMP1
expression
TAM reprogramming in lung metastases
but not in the primary tumour
198
Agonist CD40-specific
monoclonal antibodies
and gemcitabine
Pancreatic carcinoma;
human pancreatic ductal
adenocarcinoma
Targeting and activation of blood
circulating macrophages
TAM reprogramming
199
Downregulation of placental
growth factor
TAM reprogramming
200
IL‑12 production by
NK cells; TAMs become
IL‑12hiIL‑10lowMHC-IIhiARG1low
TAM reprogramming to M1 macrophage
phenotype
201
Histidine-rich glycoprotein Fibrosarcoma, pancreatic
(HRG)
cancer and breast cancer
Inhibition of NF‑κB
signalling by targeting IκB
kinase
Ovarian cancer
Refs
196,197
ARG1, arginase 1; CCL, CC‑chemokine ligand; CCR2, CC‑chemokine receptor 2; CSF1R, macrophage colony-stimulating factor receptor; CTL, cytotoxic T
lymphocyte; CXCL, CXC-chemokine ligand; DC, dendritic cell; GM‑CSF, granulocyte–macrophage colony-stimulating factor; IFNγ, interferon‑γ; IκB, NF‑κB
inhibitor; IL, interleukin; iNOS, inducible nitric oxide synthase; MDSC, myeloid-derived suppressor cell; MMP, matrix metalloproteinase; NF‑κB, nuclear factor-κB;
NK, natural killer; NO, nitric oxide; PGE2, prostaglandin E2; ROS, reactive oxygen species; SCF, stem cell factor; STAT, signal transducer and activator of
transcription; TAM, tumour-associated macrophage; TGFβ, transforming growth factor-β; TIMP1, tissue inhibitor of metalloproteinases 1; TNF, tumour necrosis
factor; VEGF, vascular endothelial growth factor. *Human cancers are indicated; other studies were conducted in mouse models.
Conclusions and perspective
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the progressing tumour? Or, do the two processes occur
concurrently and are MDSCs recruited as a pre­requisite
to tumour progression? More sophisticated tumour
models and techniques will be required to address this
key question.
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Competing interests statement
The authors declare no competing financial interests.
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