Carcinogenesis 2015 Wang Carcin Bgv123

Carcinogenesis Advance Access published September 8, 2015
Immunosuppression associated with chronic inflammation in the tumor

microenvironment
Laboratory for Inflammation and Cancer, the Biodesign Institute at Arizona State University,
Tempe, AZ 85287
2
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Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287
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Department of Research and Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259
Raymond N. DuBois, MD. Ph.D.
*Correspondence:
Executive Director of the Biodesign Institute at Arizona State University, PO Box 875001, 1001
S. McAllister Ave. Tempe, AZ 85287
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Tel: 480-965-1228 and Fax: 480-727-9550
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E-mail: duboisrn@asu.edu
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The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Downloaded from http://carcin.oxfordjournals.org/ at BIBLIOTECA CENTRAL UNIV ESTADUAL CAMPINAS on September 12, 2015
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Dingzhi Wang1 and Raymond N. DuBois1, 2, 3*
ABSTRACT
Chronic inflammation contributes to cancer development via multiple mechanisms. One
potential mechanism is that chronic inflammation can generate an immunosuppressive
The
immunosuppressive environment in certain chronic inflammatory diseases and solid cancers is
characterized by accumulation of pro-inflammatory mediators, infiltration of immune suppressor

cells, and activation of immune checkpoint pathways in effector T cells.
In this review, we
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highlight recent advances in our understanding of how immunosuppression contributes to cancer
and how pro-inflammatory mediators induce the immunosuppressive microenvironment via
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induction of immunosuppressive cells and activation of immune checkpoint pathways.
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microenvironment that allows advantages for tumor formation and progression.
INTRODUCTION
Inflammation is typically referred to as either acute or chronic.
Acute inflammation
caused by physical or chemical injury or by an infectious agent is meant to provide an early
This inflammatory process is self-limiting and
resolves after tissue repair or elimination of pathogens.
During the resolution of inflammation,
the levels of pro-inflammatory mediators and infiltrated immune cells decline and resolvins are
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produced. Resolvins are generated from eicosapentaenoic acid and docosahexaenoic acid via
cyclooxygenase (COX) pathway and exhibit both anti-inflammatory and pro-resolving actions.
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In contrast, chronic inflammation caused by infectious or autoimmune diseases is a prolonged

abnormal immune response that is not terminated by the normal feedback mechanisms.
Clinical and epidemiologic evidence indicates that chronic inflammation is a risk factor for several
gastrointestinal malignancies, including esophageal, gastric, hepatic, pancreatic and colorectal
cancer. For example, it has been long known that patients with persistent hepatitis B infection,
Helicobacter pylori (H. pylori) infection, or autoimmune disorders such as inflammatory bowel
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diseases (IBD) face an increased lifetime risk of developing liver, gastric, and colorectal cancer.
For example, more than 20% of patients with ulcerative colitis were reported to develop
colitis-associated colorectal cancer (CRC) within 30 years of diagnosis (Lakatos and Lakatos,
It has been estimated that chronic inflammation contributes to the development of
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2008).
approximately 15-20% of malignancies worldwide (Kuper et al., 2000). The observation that
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nonsteroidal anti-inflammatory drugs (NSAIDs) have beneficial effects on reducing the incidence,
metastasis, and mortality of various solid tumors (Algra and Rothwell, 2012; Harris, 2009;
Rothwell et al., 2012a; Rothwell et al., 2012b) supports the concept that chronic inflammation
promotes tumor initiation, growth, and progression.

It is generally thought that chronic inflammation promotes tumor initiation, progression,
and metastasis by providing a tumor-supporting microenvironment.
3
In addition, tumors are
healing process at the site of tissue injury.
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beneficial response that helps eliminate pathogens and necrotic cells as well as initiates the
referred to as wounds that do not heal and chronic inflammation is clearly found in the tumor
microenvironment that is probably initiated by the presence of malignant cells. The common
pathological features of chronic inflammatory diseases and solid cancers include elevation of
infiltration of deregulated immune cells, and recruitment of endothelial cells and fibroblasts
(Neuman, 2007; Sands, 2007; Strober et al., 2007).
The pro-inflammatory mediators
orchestrate cross talk between various cells to create a tumor-supporting microenvironment,
progression.
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including immunosuppression and angiogenesis, which allows tumor formation, growth, and
In this review, we mainly focus on recent insights of how chronic inflammation
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contributes to tumor initiation and how immunosuppression induced by chronic inflammation and
malignant cells promotes tumor growth and progression.
Understanding these mechanisms
may provide a rationale for developing more effective therapeutic strategies to eliminate cancer
stem-like cells (CSLCs) and to subvert tumor-induced immunosuppression for patients with
cancer.
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INFLAMMATORY MICROENVIRONMENT
In the normal gut, the immune system maintains a balance between tolerance to gut flora
and protection from harmful pathogens by providing multiple safeguards for immune
In IBD, chronic inflammation is thought to result from disruption of immune
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homeostasis.
homeostasis in response to the gut flora, which contains foreign luminal antigens from food and
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commensal bacteria. The common pathological changes associated with chronic inflammation
in IBD, H. pylori-associated gastritis, and autoimmune gastritis include elevation of
pro-inflammatory mediators, massive infiltration of dysregulated immune cells, and diminished
epithelial barrier integrity. This inflammatory microenvironment is thought to initiate epithelial

cell transformation and to promote tumor growth and progression (Noonan et al., 2008).
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pro-inflammatory mediators such as cytokines, chemokines, and prostaglandins, massive
Although the molecular mechanisms underlying contribution of chronic inflammation to

carcinogenesis are not fully understood, NF-B signaling and certain cytokines such as IL-6,
IL-17, IL-22, and IL-23 have been shown to be essential to link inflammation to tumorigenesis in
al., 2013a). H. pylori infection that is associated with gastric chronic inflammation and cancer
activates NF-B, which in turn induces pro-inflammatory genes such as IL-1, IL-6, IL-8 (CXCL8),
TNF, and COX-2 as well as inducible nitric oxide synthase and VEGF (Chung and Lim, 2014).
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These pro-inflammatory mediators can induce expression of chemokines that are responsible for
recruitment of leukocytes from the circulation system to local tissue sites.
For example, a
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recent study showed that COX-2-derived prostaglandin E2 (PGE2) secreted from mouse colonic
epithelial calls and macrophages stimulated macrophages to produce CXCL1, CCL2, CCL3,
CCL4, IL-6, and IL-1 in a mouse model of IBD (Wang et al., 2014). CXCL1, CCL2, CCL3, and
CCL4 were shown to correlate with the severity of disease in IBD patients (Wang et al., 2009).
Genetic and pharmacologic studies have demonstrated that CXCL1, CCL2, CCL3, or CCL4
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signaling promotes inflammation in models of injury-induced experimental colitis (Andres et al.,

2000; Katoh et al., 2013; Khan et al., 2006; Tokuyama et al., 2005).
Chronic inflammation and tumor initiation
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Chronic inflammation initiates tumor formation through induction of reactive oxygen and
nitrogen species, and/or DNA methylation. Inflammation-induced oxidative stress may increase
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the risk of developing colorectal, gastric, and liver cancer (Horiike et al., 2005; Murata et al.,
2012; Rachmilewitz et al., 1995; Rieder et al., 2003).
Reactive oxygen and nitrogen species
produced by inflammatory cells are associated with mutation of key genes such as tumor
suppressor and DNA repair genes (Hussain et al., 2000).
In addition, pro-inflammatory
mediators such as IL-6 and PGE2 stimulate tumor initiation by silencing tumor suppressor and/or
DNA repair genes via induction of DNA methylation (Gasche et al., 2011; Xia et al., 2012).
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mouse models of colitis-associated CRC (Greten et al., 2004; Grivennikov et al., 2009; Wang et
Activation of NF-B can enhance Wnt-signaling leading to the dedifferentiation of non-stem

tumor epithelial cells into tumor-initiating cells in mouse intestine (Schwitalla et al., 2013).
Chronic inflammation and immunosuppressive cells
via induction of pro-inflammatory mediators and accumulation/activation of immune suppressor

cells (Kanterman et al., 2012). One type of immune suppressor cells, myeloid-derived
suppressor cells (MDSCs), is greatly expanded in autoimmune diseases such as IBD (Haile et
Since MDSCs are a heterogenous population of immature myeloid cells including
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al., 2008).
progenitors of macrophages, dendritic cells (DCs), and granulocytes, expansion of MDSCs
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disrupts the normal homeostasis by interrupting maturation of macrophages, DCs, and

granulocytes.
inflammation and cancer (Fig. 1).
Several animal studies demonstrate that MDSCs are a targetable link between chronic
Depletion of MDSCs during colonic inflammation attenuated
colitis-associated tumorigenesis in a mouse model of IBD-associated carcinogenesis (Poh et al.,

In contrast, transfer of MDSCs promoted chronic inflammation in the colon and
2013).
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colitis-associated tumor formation, growth, and progression via suppression of colonic CD8+ T
cell cytotoxicity in vivo against tumor cells (Katoh et al., 2013). These findings suggesting that
chronic inflammation might promote tumor initiation and progression by induction of
Moreover, pro-inflammatory mediators induce MDSC
expansion and recruitment (Fig. 1).
For example, IL-1, IL-6, and PGE2 have been shown to
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immunosuppression via MDSCs.
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induce MDSC accumulation and activation (Ostrand-Rosenberg and Sinha, 2009; Wang and
DuBois, 2013). Moreover, a chemokine receptor, CXCR2, is required for infiltration of MDSCs
from the circulatory system to inflamed colonic mucosa and colitis-associated tumors in a mouse
model
of
colitis-associated
CXCL8-overexpressing
tumorigenesis
transgenic
mice
(Katoh
exacerbated
et
al.,
2013).
inflammation
and
Similarly,
promoted
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Emerging evidence indicates that chronic inflammation also induces immunosuppression
inflammation-associated tumorigenesis with more infiltration of MDSCs into colonic and gastric
mucosa in mouse models of colitis-associated carcinogenesis and H. felis-induced gastritis
(Asfaha et al., 2013).
CXCL8 is one of the CXCR2 ligands.
Stomach-specific overexpression
Collectively, these results suggest that
pro-inflammatory mediators promote chronic inflammation and inflammation-associated

tumorigenesis via MDSCs.
However, it is unclear why MDSCs in a chronic inflammatory
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environment do not function as immunosuppressive cells.
Tregs can also serve as immune suppressor cells and are mainly a subset of CD4+ T
Tregs are essential for maintaining
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cells that express high levels of CD25 and Foxp3.
self-tolerance and suppressing immune responses by regulating the activity of other immune
cells in prevention and control of autoimmune diseases (Fig. 2). The functions of Tregs are
dependent on both cell-cell contact and secretion of immunosuppressive cytokines IL-10 and
TGF (Izcue and Powrie, 2008). In contrast to MDSCs, Tregs play a key role in prevention and
control of IBD and gastritis (Fig. 2).
In IBD patients, reduction of Tregs and elevation of Th17
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cells were observed in the peripheral blood and pro-inflammatory cytokines such as IL-17a,
IL-1, and IL-6 were elevated in intestinal mucosa (Eastaff-Leung et al., 2010).
It is unclear
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whether IL-1 and/or IL-6 regulate the ratio between Tregs and Th17 cells in IBD.
In H.
pylori-infected patients, the numbers of Tregs in gastric mucosa or peripheral blood are
Moreover, in vivo
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negatively correlated with the level of inflammation (Kandulski et al., 2010).
studies have demonstrated that Tregs function as immunosuppressive cells in IBD, H.
pylori-associated gastritis, and autoimmune gastritis. Transfer of Tregs completely prevented

and ameliorated inflammation in a murine T cell transfer model of colitis (Uhlig et al., 2006).
Transfer of iTregs that were induced by treatment of nave T cells with TGF1 and IL-2 in vitro
into mice with the late stages of autoimmune gastritis suppressed disease progression (Nguyen
MDSCs into the stomach (Tu et al., 2008).
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of IL-1 in mice resulted in spontaneous gastric inflammation and cancer with infiltration of
et al., 2014). In contrast, depletion of Tregs exacerbated gastric inflammation and elevated
pro-inflammatory cytokine expression in H. pylori-infected mice (Rad et al., 2006).
These
studies suggest that Tregs play a key role in the prevention of autoimmune responses and H.
However, the function of Tregs in connecting chronic inflammation
Emerging evidence revealed that Tregs that expanded in
intestinal adenomas no longer produced IL-10 and instead switched to production of IL-17 in vivo
(Gounaris et al., 2009). The number of IL-17-producing Tregs was found to be significantly
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increased in inflamed mucosa of IBD patients compared to healthy individuals and associated
with colitis-associated tumorigenesis (Hovhannisyan et al., 2011; Kryczek et al., 2011),
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suggesting that pro-inflammatory mediators produced by chronic inflammation may convert

Tregs to IL-17-producing Tregs (Fig. 2). Indeed, IL-1-IL-1R1 signaling induced the conversion
of IL-17-producing Tregs from Tregs (Li et al., 2010; Raffin et al., 2011). Since IL-17-producing
Tregs lose their anti-inflammatory function and promote CRC development (Li and Boussiotis,
2013), it is conceivable that IL-17-producing Tregs induced by pro-inflammatory cytokines are a
potential cellular link between chronic inflammation and carcinogenesis (Fig. 2).
A recent
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observation that transient depletion of Tregs during inflammation inhibited colitis-associated

tumorigenesis in vivo (Pastille et al., 2014) supports this hypothesis.
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Inflammation and immune checkpoint molecules

T cell activation requires antigen-specific TCR stimulation and activation of an
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antigen-independent costimulatory receptor (CD28). On the other hand, co-inhibitory signals
suppress antigen-specific T cell responses.
The co-stimulatory receptor and co-inhibitory
receptors control the balance of T cell activation and tolerance (Fig. 3). Therefore, autoimmune
conditions may occur when this balance is disturbed.
Programmed death-1 (PD-1) and
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are the co-inhibitory receptors and are
to cancer remains unknown.
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pylori-associated gastritis.
mainly expressed on T cells.
Although both PD-1 and CTLA-4 function as negative regulators,
they play a non-redundant role in inhibition of immune responses. Interaction of PD-1 with its
ligands, PD-L1 and PD-L2, inhibits effector T cell activation and proliferation. Although both
antigen-presenting cells (APCs), CTLA-4 has higher affinity and avidity for B7-1 and B7-2 than
CD28.
Therefore, binding of CTLAT-4 with its ligands, B7-1 and B7-2, suppresses the early
activation and survival of nave and memory T cells by competing with CD28 binding.
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Data from animal studies suggest that the co-inhibitory signals play a key role in
controlling the progress of immune response and reduce the risk for development of chronic
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inflammation (Fig. 3). Deletion of PD-1 in neonatal thymectomized mice led to autoimmune
gastritis and hepatitis (Kido et al., 2008; Nishiura et al., 2013).
Blockage PD-1/PD-L1 signaling
resulted in CD8+ T cell-mediated intestinal inflammation by elimination of CD8+ T cell tolerance to

intestinal self-antigens (Reynoso et al., 2009). Cytokine such as IL-2, IL-7, IL-15, and IL-21
induce the expression of PD-1 in peripheral T cells and its ligands in peripheral
monocytes/macrophages (Kinter et al., 2008).
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inflammation to cancer is unknown.
The role of PD-1 signaling in connecting
One observation that elevation of PD-L1 expression in
intestinal epithelial cells of IBD patients and in gastric epithelial cells of H. pylori-infected patients
(Nakazawa et al., 2004; Wu et al., 2010) may support an idea that PD-1 signaling may mediate
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the contribution of chronic inflammation to carcinogenesis by preventing transformed epithelial

cells from CD8+ T cell attack.
Further studies are needed to test this hypothesis.
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CTLA-4 is minimally expressed on resting T cells and is induced after T cell activation.
In acute infections, CTLA-4 is transiently induced and binds to B7-1 and B7-2, competing with
CD28 binding following T cells activation, which in turn attenuates the T cell response by
counteracting CD28-mediated costimulatory signals.
In contrast, CTLA-4 is constitutively
expressed in T cells during chronic infections and cancer because of chronic antigen exposure.
CTLA-4 is also constitutively expressed on antigen-experienced memory CD4+ and CD8+ T cells
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CTLA-4 and CD28 bind to same ligands, CD80 (B7-1) and CD86 (B7-2), which are expressed in
as well as Tregs. Similarly, B7-1 is not expressed on resting APCs and is induced after APC
activation.
In contrast, B7-2 is constitutively expressed on resting APCs and it expression is
further induced after APC activation.
Inhibition of CTLA-4 signaling by its antibody, ipilimumab,
this signaling is important for maintenance of immune homeostasis in gut (Fig. 3).
However, the
role of CTLA-4 in H. pylori-associated gastritis is not clear because the results from mouse
models of H. pylori-associated gastritis are controversial.
One report showed that blockage of
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CTLA-4 accelerated gastric inflammation induced by H. pylori infection (Anderson et al., 2006),
whereas another study showed that CTLA-4 blockage reduced H. pylori-induced gastric
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inflammation (Watanabe et al., 2004). The reason for this discrepancy is not known.
work is necessary to clarify the role of CTLA-4 in autoimmune gastritis and H. pylori-induced
gastritis.
Since Tregs constitutively express CTLA-4 (Read et al., 2000; Takahashi et al., 2000),
loss of CTLA-4 in Tregs led to fatal systemic autoimmune disease (Wing et al., 2008).
Moreover, deletion of B7 in mice expressing a soluble B7-2 Ig Fc chimeric protein resulted in
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more severe colitis with reduction of Tregs (Kim et al., 2008).
Blockage of CTLA-4 by its
antibody abrogated the effect of Tregs on prevention of colitis in vivo (Read et al., 2000;
Takahashi et al., 2000).
These results demonstrate that CTLA-4 is required for Treg
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development and function in control of colitis.
Collectively, these results suggest that
checkpoint signaling is important for prevention and control of chronic inflammation.
The
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question is whether the checkpoint pathways are involved in contribution of chronic inflammation
to carcinogenesis.
TUMOR MICROENVIRONMENT
Similar to chronic inflammation, malignant cells secrete pro-inflammatory mediators
such as cytokines, chemokines, and eicosanoids that recruit and reprogram various types of
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induces bowel inflammation in patients with melanoma (Berman et al., 2010), suggesting that
pro-inflammatory
leukocytes
and
other
cells
to
establish
more
tumor-supportive
microenvironment. The tumor microenvironment not only allows tumor cells to evade from host
immunosurveillance, but also supports tumor growth, progression, and spread by inducing
Cancer immune evasion involves a shift
from Th1 to Th2 immune responses, a defective antigen-presenting cell (APC) function, impaired
cytotoxic activity of CD8+ T cells and natural killer (NK) cells, and enhancement of
immunosuppressive cells such as MDSCs and Tregs.
Here we focus on the multipronged
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immunosuppressive network that develops in the tumor microenvironment.

Myeloid-derived suppressor cells
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In healthy individuals, immature myeloid cells differentiate into mature myeloid cells
including macrophages, DCs, and granulocytes. However, this normal physiological process is
interrupted in cancer patients (Fig. 1). In general, there is small numbers of MDSCs in the
circulation (3-5%) of healthy individuals, but their numbers are significantly increased in blood
and tumor tissues of patients with cancer (Fig. 1). The levels of MDSCs in the blood and/or
tumor tissue are positively correlated with clinical cancer stage, metastatic tumor burden, or poor
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survival in patients with colon, esophageal, gastric, or pancreatic cancers (Diaz-Montero et al.,
2009; Duffy et al., 2013; Gabitass et al., 2011; Mandruzzato et al., 2009; Sun et al., 2012; Wang
et al., 2013b; Zhang et al., 2013).
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MDSCs have been shown to contribute to cancer immune evasion by suppressing
effector T cell activation, proliferation, trafficking, and viability, inhibiting NKs, and promoting
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activation and expansion of Treg cells (Gabrilovich et al., 2012). In addition, new evidence
reveals novel mechanisms by which MDSCs promote cancer progression and metastasis by
directly targeting cancer stem-like cells and tumor cells (Fig. 1). MDSCs directly enhanced
CSLC formation and protected proliferating tumor cells from senescence without involvement of
T cells and NKs in vivo (Cui et al., 2013; Di Mitri et al., 2014). In tumor implantation models,
inhibition of CXCR2 by its antagonist reduced MDSCs abundance in the breast tumor (Yang et
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angiogenesis and formation of cancer like stem cells.
al., 2008).
Similarly, knockdown of CXCL1/2, ligands of CXCR2, in a breast cancer cell line is
associated with reduction of myeloid cells in the tumor (Acharyya et al., 2012). These results
suggest that CXCR2 is required for infiltration of MDSCs into tumor sites.
induction of MDSC accumulation and inhibition of MDSC differentiation (Cheng et al., 2008). In
addition, IL-1, IL-6, and PGE2 secreted by tumor cells and/or their stromal cells also induce
MDSC accumulation and/or activation in tumor microenvironment (Ostrand-Rosenberg and

IL-1 and IL-6 promote the expansion of
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Sinha, 2009; Wang and DuBois, 2013) (Fig. 1).
MDSCs by induction of myelopoiesis and inhibition of the differentiation of mature myeloid cells
Furthermore, IL-1 activated MDSCs via an
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via STAT3 (Gabrilovich and Nagaraj, 2009).
IL-1RI-NF-B pathway in gastric inflammation and cancer (Tu et al., 2008), whereas IL-6
activated breast cancer-infiltrating MDSCs via a STAT3-NF-B-IDO pathway in (Yu et al., 2014).
Other cytokines and growth factors such as IFN, IL-4, IL-13, and TGF mainly secreted from
In addition, miR-155 and miR-21 may mediate the effects of GM-CSF and IL-6
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Nagaraj, 2009).
tumor cell death and T cells have been shown to activate MDSCs via STAT3 (Gabrilovich and
on induction of MDSCs from mouse bone marrow cells (Li et al., 2014).
In addition to pro-inflammatory cytokines, inflammatory PGE2 also plays a central role in
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regulation of MDSC accumulation and activation (Fig. 1).
PGE2 promoted tumor growth via
inducing the differentiation of MDSCs from bone marrow myeloid progenitor cells, whereas
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inhibition of PGE2 signaling by deletion of EP2 or its antagonists blocked this differentiation in
mice with implanted with 4T1 mammary carcinoma (Sinha et al., 2007). PGE2 has been shown
to convert DCs to MDSCs in vitro (Obermajer et al., 2011).
PGE2 directly activated
MDSC-mediated T cell suppression by induction of arginase I expression via EP4 (Rodriguez et

al., 2005).
Reduction of PGE2 levels in mesothelioma-bearing mice by celecoxib treatment
suppressed MDSC accumulation and activation (Veltman et al., 2010).
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Inhibition of
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Pro-inflammatory proteins S100A8/9 have been shown to promote tumor growth by
tumor-derived PGE2 by silencing COX-2 in 4T1 cancer cells reduced the accumulation of
MDSCs in the spleen (Mao et al., 2014).
One potential mechanism responsible for PGE2
induction of MDSC accumulation could be that PGE2 induces chemokines that attract MDSCs
NSAIDs
inhibits gliomagenesis
by
reducing
infiltration of
microenvironment via CCL2 in vivo (Fujita et al., 2011).
MDSCs
into
tumor
PGE2 has also shown to induce
CXCR2 ligand expression in inflamed colonic mucosa and colitis-associated tumor of
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AOM/DSS-treated mice as well as intestinal mucosa and tumors of Apcmin/+ mice (Katoh et al.,
2013), suggesting that PGE2 induces an infiltration of MDSCs into sites of inflammation and in
Further studies are needed to test this
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solid tumors through induction of CXCR2 ligands.

hypothesis.
Regulatory T cells
In contrast to autoimmune diseases, Tregs are thought to contribute to cancer-induced

immunosuppression by suppressing effector T cells, NKs, and DCs. The frequency of Tregs is
elevated in the peripheral blood and at the tumor sites of patients with esophageal, gastric, or
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colorectal cancers (Ichihara et al., 2003; Mizukami et al., 2008; Wolf et al., 2003) and
tumor-infiltrating Tregs correlate with poor prognosis in esophageal, gastric, and ovarian cancers
(Curiel et al., 2004; Kono et al., 2006). In tumor-bearing mice, depletion of Tregs resulted in
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regression of many tumors, including CRC, by evoking immunosurveillance, whereas adoptive

transfer of Tregs suppressed CD8+ T cell cytotoxicity against tumor (Antony et al., 2005; Casares
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et al., 2003; Onizuka et al., 1999; Shimizu et al., 1999; Turk et al., 2004). These findings
indicate that Tregs promote tumor escape from cytotoxic immune responses (Fig. 2).
Tumor-infiltrated Tregs include infiltration of thymus-derived CD4+CD25+FoxP3+ T cells,
local expansion of Tregs, and local differentiation from CD4+ T cells.
CCL22 has been shown to
recruit Tregs into tumors via its receptor, CCR4 (Curiel et al., 2004; Gobert et al., 2009).
Treatment with CCR4 antagonists enhanced the efficacy of cancer vaccines against tumor
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into the tumor microenvironment from the circulation. Indeed, deletion of COX-2 or treatment
growth by reduction of infiltration of Tregs (Pere et al., 2011).
Moreover, CCL17 and CCL22 are
correlated with Treg infiltration in gastric cancer (Mizukami et al., 2008).
In addition, CCL5
secreted from CRC is not only required for infiltration of Tregs into tumors, but also enhances
Neutralization of CCL5 inhibited the infiltration of Tregs into tumors (Tan et al., 2011). These
studies suggest that chemokines such as CCL5, CCL17, and/or CCL22 mediate the trafficking of
Tregs into tumor microenvironment (Fig. 2). In addition to infiltration of Tregs into tumors,
2005).
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TGF-secreting DCs in tumor microenvironment induces Tregs proliferation (Ghiringhelli et al.,
In vitro studies further revealed that TGF secreted from tumor cells converts
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CD4+CD25- T cells into Tregs (Liu et al., 2007) (Fig. 2). Treatment of patients with melanoma or
renal cell carcinoma (RCC) with IL-2 increased Tregs in blood and/or tumors (Ahmadzadeh and
Rosenberg, 2006; Jensen et al., 2009). In contrast, anti-VEGF-A treatment reduced peripheral
Treg proliferation in CRC patients and CRC-bearing mice (Terme et al., 2013).
Similarly, PGE2
PGE2 can
secreted from mature DCs attracted Tregs via CCL22 (Muthuswamy et al., 2008).
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also directly enhance the differentiation of nave CD4+ T cells into Tregs in vitro and induce Treg
activation in lung cancer in vivo (Baratelli et al., 2005; Sharma et al., 2005) (Fig. 2).
Deletion of
mPges-1 gene suppressed AOM-induced colon carcinogenesis accompanied with reduced
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frequency of Tregs in the draining mesenteric lymph nodes and lowered serum PGE2 levels
(Nakanishi et al., 2011). In addition, treatment with an EP4 antagonist resulted in a decreased
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number of Tregs in LNs and the skin after UV irradiation (Soontrapa et al., 2011). These results
indicate that PGE2 may enhance tumor growth via Tregs.
Although the role of Tregs in tumor
microenvironment is well established, their functions in connecting chronic inflammation to

cancer are not known.
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cytotoxicity of Tregs against CD8+ T cells via induction of TGF- in vivo (Chang et al., 2012).
Immune checkpoint molecules

Beside the role of MDSCs and Tregs in tumor-induced immunosuppression, malignant
cells can also escape from immunosurveillance by directly impairing cytotoxic activity and
PD-1 is transiently
induced in activated T cells (Barber et al., 2006) and its expression is maintained in
tumor-infiltrating effector T cells (Ahmadzadeh et al., 2009; Fourcade et al., 2009; Mumprecht et
al., 2009).
PD-L1 expression is elevated in various human cancers, including lung, colon, head
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and neck, and ovarian cancers as well as melanomas (Dong et al., 2002; Strome et al., 2003;
Zhu et al., 2014) and its expression is associated with poor prognosis among patients with
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esophageal, colon, ovarian or renal-cell cancers (Hamanishi et al., 2007; Ohigashi et al., 2005;
Song et al., 2013; Thompson et al., 2005).
Although transgenic mice with PD-L1 expression
driven by the keratin-14 promoter did not develop skin cancer spontaneously, these mice were
much more sensitive to carcinogen-induced skin cancer formation (Cao et al., 2011). These
findings suggest that the PD-1 signaling plays an important role in tumor-induced immune
evasion and that PD-1 and PD-L1 are promising immunotherapeutic targets for cancer patients
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(Fig. 3). Indeed, recent clinical trials have demonstrated that blockage of PD-1 signaling by
anti-PD-1 or anti-PD-L1 antibodies are benefits for patients with advanced melanoma, RCC, or
non-small cell lung cancer (NSCLC) (Kyi and Postow, 2014).
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Emerging evidence further revealed that oncogenes, tumor suppressive genes, and
pro-inflammatory cytokines regulate PD-L1 expression.
Elevated PD-L1 expression is
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associated with EGFR mutations in both human and mouse non-small cell lung cancer (Akbay et
al., 2013; Azuma et al., 2014). Although previous studies reveal that PD-L1 is expressed in
immune cells, recent studies show that it is also aberrantly expressed in cancer cells.
High
levels of PD-L1 on cancer cells are one potential mechanism underlying tumor evasion from
immunosurveillance.
In vitro studies demonstrated that loss of PTEN resulted in induction of
PD-L1 expression in glioma and CRC cells (Parsa et al., 2007; Song et al., 2013) and
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proliferation of CD8+ T cells through PD-1 and CTLA-4 receptors (Fig. 3).
overexpression of mutated EGFR led to induction of PD-L1 in immortalized bronchial epithelial

cells (Akbay et al., 2013). INF is also able to induce PD-L1 expression in lung, ovarian, and
colon cancer cell lines (Dong et al., 2002).
In addition, TLR4 signaling induced PD-L1
of PD-L2 expression in human cancer is available.
Little is known about how oncogenes, tumor suppressive genes, and pro-inflammatory
mediators regulate CTLA-4 and its ligands.
Similar to antibodies against PD-1 and its ligands,
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the antibodies against CTLA-4, including ipilimumab and tremelimumab, have been evaluated in
multiple clinical trials and demonstrated significant promise in treatment of advanced melanoma,
Ipilimumab is the first
an
NSCLC, RCC, and prostate cancer (Kyi and Postow, 2014) (Fig. 3).
immune checkpoint blocking antibody approved by FDA in 2011 for patients with metastatic
Although immunotherapies with these immune checkpoint antibodies against PD-1,
melanoma.
PD-L1, and CTLA-4 offer great promise for treatment of many malignancies, the objective
response rate of these antibodies is less than 30% in patients with melanoma, RCC, and NSCLC
and few responses observed in patients with colorectal, pancreatic, gastric, or breast cancer (Kyi
pt
e
and Postow, 2014). These agents seem more effective when the mutational burden is high in
the primary cancer or when T cells have infiltrated into the tumor microenvironment.
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CONCLUSION AND PERSPECTIVE

The standard treatment such as chemotherapy and radiotherapy for advanced
Ac
malignancies has improved over the past decades, but clinical outcomes havent improved as
much as we would like because these therapies only target tumor cells and are associated with
numerous side effects.
Immunotherapy with immune checkpoint inhibitors is a promising
approache for cancer treatment. However, the success rates are somewhat limited because of
immunosppressive tumor microenvironment.
A growing body of evidence supports the
16
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expression via MAPK pathways in bladder cells (Qian et al., 2008). However, little information
hypothesis that effective therapies should include elimination of tumor cells, subverting
tumor-induced immunosuppression by targeting immunosuppressive cells, and reactivation of
tumor-inhibited effector T cells by checkpoint inhibitors. Inhibition of immunosuppressive tumor
responses and enhance anti-tumor effects of chemotherapeutic agents. Targeting MDSCs and
Tregs by inactivation or depletion is not feasible now because no specific surface markers of
these cells have yet been identified.
However, recent in vivo studies showed that inhibition of
us
tumor-infiltrating MDSCs by targeting CXCR2 enhanced anti-PD1 efficacy in rhabdomyosarcoma

in vivo (Highfill et al., 2014) and improved the efficacy of chemotherapy in a spontaneous mouse
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model of prostate cancer (Di Mitri et al., 2014). These findings suggest that inhibition of MDSC
trafficking into tumor microenvironment by targeting CXCR2 will be expected to not only enhance
efficacy of immune checkpoint inhibitors or chemotherapeutic agents, but also to have benefits
for cancer patients who did not respond to treatment of checkpoint inhibitors. Finally, rational
design of combination strategies relies on better understanding of the complexity of the
pt
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immunosuppressive mechanisms in each cancer type and an accounting for individual variation.
ACKNOWLEDGEMENTS
This work is supported, in part, by the NIH R01 DK47297 NCI R01 CA184820, and P01
We thank the National Colorectal Cancer Research Alliance (NCCRA) for its
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CA77839.
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generous support (R.N.D.).
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microenvironment by targeting immunosuppressive cells would facilitate anti-tumor immune
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Carcinogenesis Advance Access published September 8, 2015

Immunosuppression associated with chronic inflammation in the tumor

Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287

Department of Research and Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259

Raymond N. DuBois, MD. Ph.D.

S. McAllister Ave. Tempe, AZ 85287

Tel: 480-965-1228 and Fax: 480-727-9550

Dingzhi Wang1 and Raymond N. DuBois1, 2, 3*

immunosuppressive environment in certain chronic inflammatory diseases and solid cancers is

characterized by accumulation of pro-inflammatory mediators, infiltration of immune suppressor

highlight recent advances in our understanding of how immunosuppression contributes to cancer

and how pro-inflammatory mediators induce the immunosuppressive microenvironment via

induction of immunosuppressive cells and activation of immune checkpoint pathways.

microenvironment that allows advantages for tumor formation and progression.

caused by physical or chemical injury or by an infectious agent is meant to provide an early

This inflammatory process is self-limiting and

resolves after tissue repair or elimination of pathogens.

During the resolution of inflammation,

In contrast, chronic inflammation caused by infectious or autoimmune diseases is a prolonged

promotes tumor initiation, growth, and progression.

In addition, tumors are

healing process at the site of tissue injury.

The pro-inflammatory mediators

orchestrate cross talk between various cells to create a tumor-supporting microenvironment,

In this review, we mainly focus on recent insights of how chronic inflammation

Understanding these mechanisms

epithelial barrier integrity. This inflammatory microenvironment is thought to initiate epithelial

pro-inflammatory mediators such as cytokines, chemokines, and prostaglandins, massive

Although the molecular mechanisms underlying contribution of chronic inflammation to

signaling promotes inflammation in models of injury-induced experimental colitis (Andres et al.,

Reactive oxygen and nitrogen species

suppressor and DNA repair genes (Hussain et al., 2000).

Activation of NF-B can enhance Wnt-signaling leading to the dedifferentiation of non-stem

via induction of pro-inflammatory mediators and accumulation/activation of immune suppressor

progenitors of macrophages, dendritic cells (DCs), and granulocytes, expansion of MDSCs

disrupts the normal homeostasis by interrupting maturation of macrophages, DCs, and

inflammation and cancer (Fig. 1).

colitis-associated tumorigenesis in a mouse model of IBD-associated carcinogenesis (Poh et al.,

expansion and recruitment (Fig. 1).

For example, IL-1, IL-6, and PGE2 have been shown to

immunosuppression via MDSCs.

Emerging evidence indicates that chronic inflammation also induces immunosuppression

CXCL8 is one of the CXCR2 ligands.

Collectively, these results suggest that

pro-inflammatory mediators promote chronic inflammation and inflammation-associated

However, it is unclear why MDSCs in a chronic inflammatory

environment do not function as immunosuppressive cells.

cells that express high levels of CD25 and Foxp3.

In IBD patients, reduction of Tregs and elevation of Th17

negatively correlated with the level of inflammation (Kandulski et al., 2010).

studies have demonstrated that Tregs function as immunosuppressive cells in IBD, H.

pylori-associated gastritis, and autoimmune gastritis. Transfer of Tregs completely prevented

MDSCs into the stomach (Tu et al., 2008).

suggesting that pro-inflammatory mediators produced by chronic inflammation may convert

observation that transient depletion of Tregs during inflammation inhibited colitis-associated

Inflammation and immune checkpoint molecules

antigen-independent costimulatory receptor (CD28). On the other hand, co-inhibitory signals

suppress antigen-specific T cell responses.

The co-stimulatory receptor and co-inhibitory

Programmed death-1 (PD-1) and

to cancer remains unknown.

mainly expressed on T cells.

Although both PD-1 and CTLA-4 function as negative regulators,

Blockage PD-1/PD-L1 signaling