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Immunosuppression associated with chronic inflammation in the tumor

microenvironment

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

1Laboratory for Inflammation and Cancer, the Biodesign Institute at Arizona State University,

Tempe, AZ 85287 2Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287 3Department of Research and Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259

*Correspondence:

Raymond N. DuBois, MD. Ph.D.

Executive Director of the Biodesign Institute at Arizona State University, PO Box 875001, 1001

S. McAllister Ave. Tempe, AZ 85287

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

E-mail: [email protected]

The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

Carcinogenesis Advance Access published September 8, 2015 at B

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ABSTRACT

Chronic inflammation contributes to cancer development via multiple mechanisms. One

potential mechanism is that chronic inflammation can generate an immunosuppressive

microenvironment that allows advantages for tumor formation and progression. 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

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.

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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 beneficial response that helps eliminate pathogens and necrotic cells as well as initiates the

healing process at the site of tissue injury. 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

produced. Resolvins are generated from eicosapentaenoic acid and docosahexaenoic acid via

cyclooxygenase (COX) pathway and exhibit both anti-inflammatory and pro-resolving actions. 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 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, 2008). It has been estimated that chronic inflammation contributes to the development of approximately 15-20% of malignancies worldwide (Kuper et al., 2000). The observation that 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. In addition, tumors are

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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

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

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,

including immunosuppression and angiogenesis, which allows tumor formation, growth, and

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

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.

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

homeostasis. In IBD, chronic inflammation is thought to result from disruption of immune

homeostasis in response to the gut flora, which contains foreign luminal antigens from food and

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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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

mouse models of colitis-associated CRC (Greten et al., 2004; Grivennikov et al., 2009; Wang et 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).

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

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

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

Chronic inflammation initiates tumor formation through induction of reactive oxygen and

nitrogen species, and/or DNA methylation. Inflammation-induced oxidative stress may increase

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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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

Emerging evidence indicates that chronic inflammation also induces immunosuppression

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 al., 2008). Since MDSCs are a heterogenous population of immature myeloid cells including progenitors of macrophages, dendritic cells (DCs), and granulocytes, expansion of MDSCs disrupts the normal homeostasis by interrupting maturation of macrophages, DCs, and

granulocytes.

Several animal studies demonstrate that MDSCs are a targetable link between chronic

inflammation and cancer (Fig. 1). Depletion of MDSCs during colonic inflammation attenuated colitis-associated tumorigenesis in a mouse model of IBD-associated carcinogenesis (Poh et al., 2013). In contrast, transfer of MDSCs promoted chronic inflammation in the colon and 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

immunosuppression via MDSCs. Moreover, pro-inflammatory mediators induce MDSC

expansion and recruitment (Fig. 1). For example, IL-1, IL-6, and PGE2 have been shown to

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 tumorigenesis (Katoh et al., 2013). Similarly, CXCL8-overexpressing transgenic mice exacerbated inflammation and promoted

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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

of IL-1 in mice resulted in spontaneous gastric inflammation and cancer with infiltration of

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

environment do not function as immunosuppressive cells.

Tregs can also serve as immune suppressor cells and are mainly a subset of CD4+ T

cells that express high levels of CD25 and Foxp3. Tregs are essential for maintaining

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 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

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

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

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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.

pylori-associated gastritis. However, the function of Tregs in connecting chronic inflammation

to cancer remains unknown. 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 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), 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 observation that transient depletion of Tregs during inflammation inhibited colitis-associated

tumorigenesis in vivo (Pastille et al., 2014) supports this hypothesis.

Inflammation and immune checkpoint molecules

T cell activation requires antigen-specific TCR stimulation and activation of an

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

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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

CTLA-4 and CD28 bind to same ligands, CD80 (B7-1) and CD86 (B7-2), which are expressed in 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.

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

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). The role of PD-1 signaling in connecting inflammation to cancer is unknown. 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 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.

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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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,

induces bowel inflammation in patients with melanoma (Berman et al., 2010), suggesting that 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

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

inflammation (Watanabe et al., 2004). The reason for this discrepancy is not known. Further 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

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 development and function in control of colitis. Collectively, these results suggest that

checkpoint signaling is important for prevention and control of chronic inflammation. The

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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pro-inflammatory leukocytes and other cells to establish a 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

angiogenesis and formation of cancer like stem cells. 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

immunosuppressive network that develops in the tumor microenvironment.

Myeloid-derived suppressor cells

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

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). MDSCs have been shown to contribute to cancer immune evasion by suppressing

effector T cell activation, proliferation, trafficking, and viability, inhibiting NKs, and promoting

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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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.

Pro-inflammatory proteins S100A8/9 have been shown to promote tumor growth by

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

Sinha, 2009; Wang and DuBois, 2013) (Fig. 1). IL-1 and IL-6 promote the expansion of

MDSCs by induction of myelopoiesis and inhibition of the differentiation of mature myeloid cells

via STAT3 (Gabrilovich and Nagaraj, 2009). Furthermore, IL-1 activated MDSCs via an

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

tumor cell death and T cells have been shown to activate MDSCs via STAT3 (Gabrilovich and Nagaraj, 2009). In addition, miR-155 and miR-21 may mediate the effects of GM-CSF and IL-6 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

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

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). Inhibition of

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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

into the tumor microenvironment from the circulation. Indeed, deletion of COX-2 or treatment

with NSAIDs inhibits gliomagenesis by reducing infiltration of MDSCs into tumor

microenvironment via CCL2 in vivo (Fujita et al., 2011). PGE2 has also shown to induce CXCR2 ligand expression in inflamed colonic mucosa and colitis-associated tumor of

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 solid tumors through induction of CXCR2 ligands. Further studies are needed to test this

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

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 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 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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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

cytotoxicity of Tregs against CD8+ T cells via induction of TGF- in vivo (Chang et al., 2012).

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,

TGF-secreting DCs in tumor microenvironment induces Tregs proliferation (Ghiringhelli et al.,

2005). In vitro studies further revealed that TGF secreted from tumor cells converts

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 secreted from mature DCs attracted Tregs via CCL22 (Muthuswamy et al., 2008). PGE2 can 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

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 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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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

proliferation of CD8+ T cells through PD-1 and CTLA-4 receptors (Fig. 3). 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 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 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

(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). Emerging evidence further revealed that oncogenes, tumor suppressive genes, and

pro-inflammatory cytokines regulate PD-L1 expression. Elevated PD-L1 expression is

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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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 expression via MAPK pathways in bladder cells (Qian et al., 2008). However, little information 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,

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,

NSCLC, RCC, and prostate cancer (Kyi and Postow, 2014) (Fig. 3). Ipilimumab is the first immune checkpoint blocking antibody approved by FDA in 2011 for patients with metastatic

melanoma. Although immunotherapies with these immune checkpoint antibodies against PD-1,

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 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.

CONCLUSION AND PERSPECTIVE

The standard treatment such as chemotherapy and radiotherapy for advanced

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

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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

microenvironment by targeting immunosuppressive cells would facilitate anti-tumor immune

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

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 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

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

CA77839. We thank the National Colorectal Cancer Research Alliance (NCCRA) for its generous support (R.N.D.).

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REFERENCES

Acharyya, S., Oskarsson, T., Vanharanta, S., Malladi, S., Kim, J., Morris, P.G.,

Manova-Todorova, K., Leversha, M., Hogg, N., Seshan, V.E., et al. (2012). A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165-178.

Ahmadzadeh, M., Johnson, L.A., Heemskerk, B., Wunderlich, J.R., Dudley, M.E., White, D.E.,

and Rosenberg, S.A. (2009). Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537-1544.

Ahmadzadeh, M., and Rosenberg, S.A. (2006). IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood 107, 2409-2414.

Akbay, E.A., Koyama, S., Carretero, J., Altabef, A., Tchaicha, J.H., Christensen, C.L., Mikse,

O.R., Cherniack, A.D., Beauchamp, E.M., Pugh, T.J., et al. (2013). Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer discovery 3,

1355-1363.

Algra, A.M., and Rothwell, P.M. (2012). Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus

randomised trials. The lancet oncology 13, 518-527.

Anderson, K.M., Czinn, S.J., Redline, R.W., and Blanchard, T.G. (2006). Induction of CTLA-4-mediated anergy contributes to persistent colonization in the murine model of gastric

Helicobacter pylori infection. J Immunol 176, 5306-5313.

Andres, P.G., Beck, P.L., Mizoguchi, E., Mizoguchi, A., Bhan, A.K., Dawson, T., Kuziel, W.A.,

Maeda, N., MacDermott, R.P., Podolsky, D.K., et al. (2000). Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack

of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type

immune response in the intestine. J Immunol 164, 6303-6312.

Antony, P.A., Piccirillo, C.A., Akpinarli, A., Finkelstein, S.E., Speiss, P.J., Surman, D.R., Palmer,

D.C., Chan, C.C., Klebanoff, C.A., Overwijk, W.W., et al. (2005). CD8+ T cell immunity against a

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

19

tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T

regulatory cells. J Immunol 174, 2591-2601.

Asfaha, S., Dubeykovskiy, A.N., Tomita, H., Yang, X., Stokes, S., Shibata, W., Friedman, R.A.,

Ariyama, H., Dubeykovskaya, Z.A., Muthupalani, S., et al. (2013). Mice that express human interleukin-8 have increased mobilization of immature myeloid cells, which exacerbates

inflammation and accelerates colon carcinogenesis. Gastroenterology 144, 155-166.

Azuma, K., Ota, K., Kawahara, A., Hattori, S., Iwama, E., Harada, T., Matsumoto, K., Takayama,

K., Takamori, S., Kage, M., et al. (2014). Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Annals of oncology : official

journal of the European Society for Medical Oncology / ESMO 25, 1935-1940. Baratelli, F., Lin, Y., Zhu, L., Yang, S.C., Heuze-Vourc'h, N., Zeng, G., Reckamp, K., Dohadwala,

M., Sharma, S., and Dubinett, S.M. (2005). Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 175, 1483-1490.

Barber, D.L., Wherry, E.J., Masopust, D., Zhu, B., Allison, J.P., Sharpe, A.H., Freeman, G.J., and

Ahmed, R. (2006). Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687.

Berman, D., Parker, S.M., Siegel, J., Chasalow, S.D., Weber, J., Galbraith, S., Targan, S.R., and

Wang, H.L. (2010). Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer

immunity 10, 11.

Cao, Y., Zhang, L., Kamimura, Y., Ritprajak, P., Hashiguchi, M., Hirose, S., and Azuma, M. (2011). B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. Cancer Res 71, 1235-1243.

Casares, N., Arribillaga, L., Sarobe, P., Dotor, J., Lopez-Diaz de Cerio, A., Melero, I., Prieto, J.,

Borras-Cuesta, F., and Lasarte, J.J. (2003). CD4+/CD25+ regulatory cells inhibit activation of

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

20

tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as

long-lasting tumor immunity elicited by peptide vaccination. J Immunol 171, 5931-5939.

Chang, L.Y., Lin, Y.C., Mahalingam, J., Huang, C.T., Chen, T.W., Kang, C.W., Peng, H.M., Chu,

Y.Y., Chiang, J.M., Dutta, A., et al. (2012). Tumor-derived chemokine CCL5 enhances TGF-beta-mediated killing of CD8(+) T cells in colon cancer by T-regulatory cells. Cancer Res 72, 1092-1102.

Cheng, P., Corzo, C.A., Luetteke, N., Yu, B., Nagaraj, S., Bui, M.M., Ortiz, M., Nacken, W., Sorg, C., Vogl, T., et al. (2008). Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205,

2235-2249.

Chung, H.W., and Lim, J.B. (2014). Role of the tumor microenvironment in the pathogenesis of gastric carcinoma. World journal of gastroenterology : WJG 20, 1667-1680. Cui, T.X., Kryczek, I., Zhao, L., Zhao, E., Kuick, R., Roh, M.H., Vatan, L., Szeliga, W., Mao, Y.,

Thomas, D.G., et al. (2013). Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39, 611-621.

Curiel, T.J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M.,

Conejo-Garcia, J.R., Zhang, L., Burow, M., et al. (2004). Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10,

942-949.

Di Mitri, D., Toso, A., Chen, J.J., Sarti, M., Pinton, S., Jost, T.R., D'Antuono, R., Montani, E.,

Garcia-Escudero, R., Guccini, I., et al. (2014). Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature 515, 134-137.

Diaz-Montero, C.M., Salem, M.L., Nishimura, M.I., Garrett-Mayer, E., Cole, D.J., and Montero,

A.J. (2009). Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer

Immunol Immunother 58, 49-59.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

21

Dong, H., Strome, S.E., Salomao, D.R., Tamura, H., Hirano, F., Flies, D.B., Roche, P.C., Lu, J.,

Zhu, G., Tamada, K., et al. (2002). Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8, 793-800.

Duffy, A., Zhao, F., Haile, L., Gamrekelashvili, J., Fioravanti, S., Ma, C., Kapanadze, T.,

Compton, K., Figg, W.D., and Greten, T.F. (2013). Comparative analysis of monocytic and granulocytic myeloid-derived suppressor cell subsets in patients with gastrointestinal

malignancies. Cancer Immunol Immunother 62, 299-307.

Eastaff-Leung, N., Mabarrack, N., Barbour, A., Cummins, A., and Barry, S. (2010). Foxp3+ regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease.

Journal of clinical immunology 30, 80-89.

Fourcade, J., Kudela, P., Sun, Z., Shen, H., Land, S.R., Lenzner, D., Guillaume, P., Luescher,

I.F., Sander, C., Ferrone, S., et al. (2009). PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 182, 5240-5249.

Fujita, M., Kohanbash, G., Fellows-Mayle, W., Hamilton, R.L., Komohara, Y., Decker, S.A., Ohlfest, J.R., and Okada, H. (2011). COX-2 blockade suppresses gliomagenesis by

inhibiting myeloid-derived suppressor cells. Cancer Res 71, 2664-2674.

Gabitass, R.F., Annels, N.E., Stocken, D.D., Pandha, H.A., and Middleton, G.W. (2011). Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an

independent prognostic factor and are associated with significant elevation of the Th2 cytokine

interleukin-13. Cancer Immunol Immunother 60, 1419-1430.

Gabrilovich, D.I., and Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9, 162-174.

Gabrilovich, D.I., Ostrand-Rosenberg, S., and Bronte, V. (2012). Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12, 253-268.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

22

Gasche, J.A., Hoffmann, J., Boland, C.R., and Goel, A. (2011). Interleukin-6 promotes tumorigenesis by altering DNA methylation in oral cancer cells. Int J Cancer 129, 1053-1063.

Ghiringhelli, F., Puig, P.E., Roux, S., Parcellier, A., Schmitt, E., Solary, E., Kroemer, G., Martin,

F., Chauffert, B., and Zitvogel, L. (2005). Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med

202, 919-929.

Gobert, M., Treilleux, I., Bendriss-Vermare, N., Bachelot, T., Goddard-Leon, S., Arfi, V., Biota,

C., Doffin, A.C., Durand, I., Olive, D., et al. (2009). Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors

and lead to an adverse clinical outcome. Cancer Res 69, 2000-2009.

Gounaris, E., Blatner, N.R., Dennis, K., Magnusson, F., Gurish, M.F., Strom, T.B., Beckhove, P.,

Gounari, F., and Khazaie, K. (2009). T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res 69, 5490-5497.

Greten, F.R., Eckmann, L., Greten, T.F., Park, J.M., Li, Z.W., Egan, L.J., Kagnoff, M.F., and

Karin, M. (2004). IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285-296.

Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G.Y., Vallabhapurapu, S., Scheller, J.,

Rose-John, S., Cheroutre, H., Eckmann, L., et al. (2009). IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer cell 15,

103-113.

Haile, L.A., von Wasielewski, R., Gamrekelashvili, J., Kruger, C., Bachmann, O., Westendorf,

A.M., Buer, J., Liblau, R., Manns, M.P., Korangy, F., et al. (2008). Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. Gastroenterology 135,

871-881, 881 e871-875.

Hamanishi, J., Mandai, M., Iwasaki, M., Okazaki, T., Tanaka, Y., Yamaguchi, K., Higuchi, T.,

Yagi, H., Takakura, K., Minato, N., et al. (2007). Programmed cell death 1 ligand 1 and

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

23

tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl

Acad Sci U S A 104, 3360-3365.

Harris, R.E. (2009). Cyclooxygenase-2 (cox-2) blockade in the chemoprevention of cancers of the colon, breast, prostate, and lung. Inflammopharmacology 17, 55-67.

Highfill, S.L., Cui, Y., Giles, A.J., Smith, J.P., Zhang, H., Morse, E., Kaplan, R.N., and Mackall,

C.L. (2014). Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Science translational medicine 6, 237ra267.

Horiike, S., Kawanishi, S., Kaito, M., Ma, N., Tanaka, H., Fujita, N., Iwasa, M., Kobayashi, Y., Hiraku, Y., Oikawa, S., et al. (2005). Accumulation of 8-nitroguanine in the liver of patients with chronic hepatitis C. Journal of hepatology 43, 403-410.

Hovhannisyan, Z., Treatman, J., Littman, D.R., and Mayer, L. (2011). Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with

inflammatory bowel diseases. Gastroenterology 140, 957-965.

Hussain, S.P., Amstad, P., Raja, K., Ambs, S., Nagashima, M., Bennett, W.P., Shields, P.G., Ham, A.J., Swenberg, J.A., Marrogi, A.J., et al. (2000). Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease.

Cancer Res 60, 3333-3337.

Ichihara, F., Kono, K., Takahashi, A., Kawaida, H., Sugai, H., and Fujii, H. (2003). Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients

with gastric and esophageal cancers. Clin Cancer Res 9, 4404-4408.

Izcue, A., and Powrie, F. (2008). Special regulatory T-cell review: Regulatory T cells and the intestinal tract--patrolling the frontier. Immunology 123, 6-10.

Jensen, H.K., Donskov, F., Nordsmark, M., Marcussen, N., and von der Maase, H. (2009). Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in

metastatic renal cell carcinoma. Clin Cancer Res 15, 1052-1058.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

24

Kandulski, A., Malfertheiner, P., and Wex, T. (2010). Role of regulatory T-cells in H. pylori-induced gastritis and gastric cancer. Anticancer Res 30, 1093-1103.

Kanterman, J., Sade-Feldman, M., and Baniyash, M. (2012). New insights into chronic inflammation-induced immunosuppression. Seminars in cancer biology 22, 307-318.

Katoh, H., Wang, D., Daikoku, T., Sun, H., Dey, S.K., and Dubois, R.N. (2013). CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated

tumorigenesis. Cancer Cell 24, 631-644.

Khan, W.I., Motomura, Y., Wang, H., El-Sharkawy, R.T., Verdu, E.F., Verma-Gandhu, M.,

Rollins, B.J., and Collins, S.M. (2006). Critical role of MCP-1 in the pathogenesis of experimental colitis in the context of immune and enterochromaffin cells. Am J Physiol Gastrointest Liver

Physiol 291, G803-811.

Kido, M., Watanabe, N., Okazaki, T., Akamatsu, T., Tanaka, J., Saga, K., Nishio, A., Honjo, T., and Chiba, T. (2008). Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology 135, 1333-1343.

Kim, G., Turovskaya, O., Levin, M., Byrne, F.R., Whoriskey, J.S., McCabe, J.G., and

Kronenberg, M. (2008). Spontaneous colitis occurrence in transgenic mice with altered B7-mediated costimulation. J Immunol 181, 5278-5288.

Kinter, A.L., Godbout, E.J., McNally, J.P., Sereti, I., Roby, G.A., O'Shea, M.A., and Fauci, A.S.

(2008). The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 181, 6738-6746.

Kono, K., Kawaida, H., Takahashi, A., Sugai, H., Mimura, K., Miyagawa, N., Omata, H., and Fujii, H. (2006). CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 55, 1064-1071.

Kryczek, I., Wu, K., Zhao, E., Wei, S., Vatan, L., Szeliga, W., Huang, E., Greenson, J., Chang,

A., Rolinski, J., et al. (2011). IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol 186, 4388-4395.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

25

Kuper, H., Adami, H.O., and Trichopoulos, D. (2000). Infections as a major preventable cause of human cancer. J Intern Med 248, 171-183.

Kyi, C., and Postow, M.A. (2014). Checkpoint blocking antibodies in cancer immunotherapy. FEBS letters 588, 368-376.

Lakatos, P.L., and Lakatos, L. (2008). Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World journal of gastroenterology : WJG 14, 3937-3947. Li, L., and Boussiotis, V.A. (2013). The role of IL-17-producing Foxp3+ CD4+ T cells in inflammatory bowel disease and colon cancer. Clinical immunology 148, 246-253.

Li, L., Kim, J., and Boussiotis, V.A. (2010). IL-1beta-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells. J Immunol

185, 4148-4153.

Li, L., Zhang, J., Diao, W., Wang, D., Wei, Y., Zhang, C.Y., and Zen, K. (2014). MicroRNA-155 and MicroRNA-21 promote the expansion of functional myeloid-derived suppressor cells. J

Immunol 192, 1034-1043.

Liu, V.C., Wong, L.Y., Jang, T., Shah, A.H., Park, I., Yang, X., Zhang, Q., Lonning, S., Teicher,

B.A., and Lee, C. (2007). Tumor evasion of the immune system by converting CD4+CD25- T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J Immunol 178,

2883-2892.

Mandruzzato, S., Solito, S., Falisi, E., Francescato, S., Chiarion-Sileni, V., Mocellin, S., Zanon,

A., Rossi, C.R., Nitti, D., Bronte, V., et al. (2009). IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. J Immunol 182, 6562-6568.

Mao, Y., Sarhan, D., Steven, A., Seliger, B., Kiessling, R., and Lundqvist, A. (2014). Inhibition of tumor-derived prostaglandin-e2 blocks the induction of myeloid-derived suppressor cells and

recovers natural killer cell activity. Clin Cancer Res 20, 4096-4106.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

26

Mizukami, Y., Kono, K., Kawaguchi, Y., Akaike, H., Kamimura, K., Sugai, H., and Fujii, H. (2008). CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of

Foxp3+ regulatory T cells in gastric cancer. Int J Cancer 122, 2286-2293.

Mumprecht, S., Schurch, C., Schwaller, J., Solenthaler, M., and Ochsenbein, A.F. (2009). Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell

exhaustion and disease progression. Blood 114, 1528-1536.

Murata, M., Thanan, R., Ma, N., and Kawanishi, S. (2012). Role of nitrative and oxidative DNA damage in inflammation-related carcinogenesis. Journal of biomedicine & biotechnology 2012,

623019.

Muthuswamy, R., Urban, J., Lee, J.J., Reinhart, T.A., Bartlett, D., and Kalinski, P. (2008). Ability of mature dendritic cells to interact with regulatory T cells is imprinted during maturation. Cancer

Res 68, 5972-5978.

Nakanishi, M., Menoret, A., Tanaka, T., Miyamoto, S., Montrose, D.C., Vella, A.T., and

Rosenberg, D.W. (2011). Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity. Cancer Prev Res (Phila) 4, 1198-1208. Nakazawa, A., Dotan, I., Brimnes, J., Allez, M., Shao, L., Tsushima, F., Azuma, M., and Mayer,

L. (2004). The expression and function of costimulatory molecules B7H and B7-H1 on colonic epithelial cells. Gastroenterology 126, 1347-1357.

Neuman, M.G. (2007). Immune dysfunction in inflammatory bowel disease. Transl Res 149, 173-186.

Nguyen, T.L., Makhlouf, N.T., Anthony, B.A., Teague, R.M., and DiPaolo, R.J. (2014). In vitro induced regulatory T cells are unique from endogenous regulatory T cells and effective at

suppressing late stages of ongoing autoimmunity. PloS one 9, e104698.

Nishiura, H., Iwamoto, S., Kido, M., Aoki, N., Maruoka, R., Ikeda, A., Chiba, T., and Watanabe,

N. (2013). Interleukin-21 and tumor necrosis factor-alpha are critical for the development of autoimmune gastritis in mice. J Gastroenterol Hepatol 28, 982-991.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

27

Noonan, D.M., De Lerma Barbaro, A., Vannini, N., Mortara, L., and Albini, A. (2008). Inflammation, inflammatory cells and angiogenesis: decisions and indecisions. Cancer

Metastasis Rev 27, 31-40.

Obermajer, N., Muthuswamy, R., Lesnock, J., Edwards, R.P., and Kalinski, P. (2011). Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward

stable myeloid-derived suppressor cells. Blood 118, 5498-5505.

Ohigashi, Y., Sho, M., Yamada, Y., Tsurui, Y., Hamada, K., Ikeda, N., Mizuno, T., Yoriki, R.,

Kashizuka, H., Yane, K., et al. (2005). Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 11,

2947-2953.

Onizuka, S., Tawara, I., Shimizu, J., Sakaguchi, S., Fujita, T., and Nakayama, E. (1999). Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59, 3128-3133.

Ostrand-Rosenberg, S., and Sinha, P. (2009). Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182, 4499-4506.

Parsa, A.T., Waldron, J.S., Panner, A., Crane, C.A., Parney, I.F., Barry, J.J., Cachola, K.E.,

Murray, J.C., Tihan, T., Jensen, M.C., et al. (2007). Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13, 84-88.

Pastille, E., Bardini, K., Fleissner, D., Adamczyk, A., Frede, A., Wadwa, M., von Smolinski, D.,

Kasper, S., Sparwasser, T., Gruber, A.D., et al. (2014). Transient ablation of regulatory T cells improves antitumor immunity in colitis-associated colon cancer. Cancer Res 74, 4258-4269.

Pere, H., Montier, Y., Bayry, J., Quintin-Colonna, F., Merillon, N., Dransart, E., Badoual, C., Gey,

A., Ravel, P., Marcheteau, E., et al. (2011). A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens. Blood 118, 4853-4862.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

28

Poh, T.W., Madsen, C.S., Gorman, J.E., Marler, R.J., Leighton, J.A., Cohen, P.A., and Gendler,

S.J. (2013). Downregulation of hematopoietic MUC1 during experimental colitis increases tumor-promoting myeloid-derived suppressor cells. Clin Cancer Res 19, 5039-5052.

Qian, Y., Deng, J., Geng, L., Xie, H., Jiang, G., Zhou, L., Wang, Y., Yin, S., Feng, X., Liu, J., et al.

(2008). TLR4 signaling induces B7-H1 expression through MAPK pathways in bladder cancer cells. Cancer investigation 26, 816-821.

Rachmilewitz, D., Stamler, J.S., Bachwich, D., Karmeli, F., Ackerman, Z., and Podolsky, D.K.

(1995). Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Gut 36, 718-723.

Rad, R., Brenner, L., Bauer, S., Schwendy, S., Layland, L., da Costa, C.P., Reindl, W.,

Dossumbekova, A., Friedrich, M., Saur, D., et al. (2006). CD25+/Foxp3+ T cells regulate gastric inflammation and Helicobacter pylori colonization in vivo. Gastroenterology 131, 525-537.

Raffin, C., Raimbaud, I., Valmori, D., and Ayyoub, M. (2011). Ex vivo IL-1 receptor type I expression in human CD4+ T cells identifies an early intermediate in the differentiation of Th17

from FOXP3+ naive regulatory T cells. J Immunol 187, 5196-5202.

Read, S., Malmstrom, V., and Powrie, F. (2000). Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192, 295-302.

Reynoso, E.D., Elpek, K.G., Francisco, L., Bronson, R., Bellemare-Pelletier, A., Sharpe, A.H.,

Freeman, G.J., and Turley, S.J. (2009). Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J Immunol 182, 2102-2112.

Rieder, G., Hofmann, J.A., Hatz, R.A., Stolte, M., and Enders, G.A. (2003). Up-regulation of inducible nitric oxide synthase in Helicobacter pylori-associated gastritis may represent an

increased risk factor to develop gastric carcinoma of the intestinal type. International journal of medical microbiology : IJMM 293, 403-412.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

29

Rodriguez, P.C., Hernandez, C.P., Quiceno, D., Dubinett, S.M., Zabaleta, J., Ochoa, J.B.,

Gilbert, J., and Ochoa, A.C. (2005). Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202, 931-939.

Rothwell, P.M., Price, J.F., Fowkes, F.G., Zanchetti, A., Roncaglioni, M.C., Tognoni, G., Lee, R.,

Belch, J.F., Wilson, M., Mehta, Z., et al. (2012a). Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in

51 randomised controlled trials. Lancet 379, 1602-1612.

Rothwell, P.M., Wilson, M., Price, J.F., Belch, J.F., Meade, T.W., and Mehta, Z. (2012b). Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised

controlled trials. Lancet 379, 1591-1601.

Sands, B.E. (2007). Inflammatory bowel disease: past, present, and future. J Gastroenterol 42, 16-25.

Schwitalla, S., Fingerle, A.A., Cammareri, P., Nebelsiek, T., Goktuna, S.I., Ziegler, P.K., Canli,

O., Heijmans, J., Huels, D.J., Moreaux, G., et al. (2013). Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25-38.

Sharma, S., Yang, S.C., Zhu, L., Reckamp, K., Gardner, B., Baratelli, F., Huang, M., Batra, R.K.,

and Dubinett, S.M. (2005). Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65,

5211-5220.

Shimizu, J., Yamazaki, S., and Sakaguchi, S. (1999). Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol

163, 5211-5218.

Sinha, P., Clements, V.K., Fulton, A.M., and Ostrand-Rosenberg, S. (2007). Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67,

4507-4513.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

30

Song, M., Chen, D., Lu, B., Wang, C., Zhang, J., Huang, L., Wang, X., Timmons, C.L., Hu, J.,

Liu, B., et al. (2013). PTEN loss increases PD-L1 protein expression and affects the correlation between PD-L1 expression and clinical parameters in colorectal cancer. PloS one 8, e65821.

Soontrapa, K., Honda, T., Sakata, D., Yao, C., Hirata, T., Hori, S., Matsuoka, T., Kita, Y.,

Shimizu, T., Kabashima, K., et al. (2011). Prostaglandin E2-prostaglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression. Proc Natl Acad Sci U S A 108, 6668-6673.

Strober, W., Fuss, I., and Mannon, P. (2007). The fundamental basis of inflammatory bowel disease. J Clin Invest 117, 514-521.

Strome, S.E., Dong, H., Tamura, H., Voss, S.G., Flies, D.B., Tamada, K., Salomao, D., Cheville,

J., Hirano, F., Lin, W., et al. (2003). B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 63, 6501-6505.

Sun, H.L., Zhou, X., Xue, Y.F., Wang, K., Shen, Y.F., Mao, J.J., Guo, H.F., and Miao, Z.N.

(2012). Increased frequency and clinical significance of myeloid-derived suppressor cells in human colorectal carcinoma. World journal of gastroenterology : WJG 18, 3303-3309. Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T.W., and

Sakaguchi, S. (2000). Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192,

303-310.

Tan, W., Zhang, W., Strasner, A., Grivennikov, S., Cheng, J.Q., Hoffman, R.M., and Karin, M.

(2011). Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548-553.

Terme, M., Pernot, S., Marcheteau, E., Sandoval, F., Benhamouda, N., Colussi, O., Dubreuil, O.,

Carpentier, A.F., Tartour, E., and Taieb, J. (2013). VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 73, 539-549.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

31

Thompson, R.H., Webster, W.S., Cheville, J.C., Lohse, C.M., Dong, H., Leibovich, B.C., Kuntz,

S.M., Sengupta, S., Kwon, E.D., and Blute, M.L. (2005). B7-H1 glycoprotein blockade: a novel strategy to enhance immunotherapy in patients with renal cell carcinoma. Urology 66, 10-14.

Tokuyama, H., Ueha, S., Kurachi, M., Matsushima, K., Moriyasu, F., Blumberg, R.S., and Kakimi,

K. (2005). The simultaneous blockade of chemokine receptors CCR2, CCR5 and CXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated

colitis. Int Immunol 17, 1023-1034.

Tu, S., Bhagat, G., Cui, G., Takaishi, S., Kurt-Jones, E.A., Rickman, B., Betz, K.S.,

Penz-Oesterreicher, M., Bjorkdahl, O., Fox, J.G., et al. (2008). Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived

suppressor cells in mice. Cancer cell 14, 408-419.

Turk, M.J., Guevara-Patino, J.A., Rizzuto, G.A., Engelhorn, M.E., Sakaguchi, S., and Houghton,

A.N. (2004). Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 200, 771-782.

Uhlig, H.H., Coombes, J., Mottet, C., Izcue, A., Thompson, C., Fanger, A., Tannapfel, A.,

Fontenot, J.D., Ramsdell, F., and Powrie, F. (2006). Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol 177, 5852-5860.

Veltman, J.D., Lambers, M.E., van Nimwegen, M., Hendriks, R.W., Hoogsteden, H.C., Aerts,

J.G., and Hegmans, J.P. (2010). COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib

influences MDSC function. BMC Cancer 10, 464.

Wang, D., and DuBois, R.N. (2013). An inflammatory mediator, prostaglandin E2, in colorectal cancer. Cancer journal 19, 502-510. Wang, D., Dubois, R.N., and Richmond, A. (2009). The role of chemokines in intestinal inflammation and cancer. Curr Opin Pharmacol 9, 688-696.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

32

Wang, D., Fu, L., Ning, W., Guo, L., Sun, X., Dey, S.K., Chaturvedi, R., Wilson, K.T., and DuBois,

R.N. (2014). Peroxisome proliferator-activated receptor delta promotes colonic inflammation and tumor growth. Proc Natl Acad Sci U S A 111, 7084-7089.

Wang, K., Grivennikov, S.I., and Karin, M. (2013a). Implications of anti-cytokine therapy in colorectal cancer and autoimmune diseases. Annals of the rheumatic diseases 72 Suppl 2,

ii100-103.

Wang, L., Chang, E.W., Wong, S.C., Ong, S.M., Chong, D.Q., and Ling, K.L. (2013b). Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma

S100A8/A9 proinflammatory proteins. J Immunol 190, 794-804.

Watanabe, K., Murakami, K., Sato, R., Okimoto, T., Maeda, K., Nasu, M., Nishizono, A., and

Fujioka, T. (2004). CTLA-4 blockade inhibits induction of Helicobacter pylori-associated gastritis in mice. Clin Exp Immunol 135, 29-34.

Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., and

Sakaguchi, S. (2008). CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271-275.

Wolf, A.M., Wolf, D., Steurer, M., Gastl, G., Gunsilius, E., and Grubeck-Loebenstein, B. (2003). Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9,

606-612.

Wu, Y.Y., Lin, C.W., Cheng, K.S., Lin, C., Wang, Y.M., Lin, I.T., Chou, Y.H., and Hsu, P.N.

(2010). Increased programmed death-ligand-1 expression in human gastric epithelial cells in Helicobacter pylori infection. Clin Exp Immunol 161, 551-559.

Xia, D., Wang, D., Kim, S.H., Katoh, H., and DuBois, R.N. (2012). Prostaglandin E2 promotes intestinal tumor growth via DNA methylation. Nat Med 18, 224-226.

Yang, L., Huang, J., Ren, X., Gorska, A.E., Chytil, A., Aakre, M., Carbone, D.P., Matrisian, L.M.,

Richmond, A., Lin, P.C., et al. (2008). Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23-35.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

DU

AL CA

MPIN

AS on Septem


Dow

nloaded from

Acce

pted

Man

uscr

ipt

33

Yu, J., Wang, Y., Yan, F., Zhang, P., Li, H., Zhao, H., Yan, C., Yan, F., and Ren, X. (2014). Noncanonical NF-kappaB activation mediates STAT3-stimulated IDO upregulation in

myeloid-derived suppressor cells in breast cancer. J Immunol 193, 2574-2586.

Zhang, B., Wang, Z., Wu, L., Zhang, M., Li, W., Ding, J., Zhu, J., Wei, H., and Zhao, K. (2013). Circulating and tumor-infiltrating myeloid-derived suppressor cells in patients with colorectal

carcinoma. PloS one 8, e57114.

Zhu, J., Chen, L., Zou, L., Yang, P., Wu, R., Mao, Y., Zhou, H., Li, R., Wang, K., Wang, W., et al.

(2014). MiR-20b, -21, and -130b inhibit PTEN expression resulting in B7-H1 over-expression in advanced colorectal cancer. Human immunology 75, 348-353.

at BIB

LIOTECA

CENTRA

L UN

IV ESTA

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