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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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