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Immunobiology journal homepage: www.elsevier.com/locate/imbio

Review

Myeloid regulatory cells in tumor spreading and metastasis Anton A. Keskinov ∗ , Michael R. Shurin Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

a r t i c l e

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Article history: Received 10 June 2014 Received in revised form 14 July 2014 Accepted 15 July 2014 Available online xxx Keywords: MDSC Cancer Metastasis Tumor microenvironment Immunosuppression

a b s t r a c t Development of metastasis is determined by both the accretion of essential changes in cancerous cells and by their communications with different stromal elements in the tumor microenvironment. Specifically, inflammatory response and emergence of immune regulatory cells, such and myeloid regulatory cells (macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells) and lymphoid regulatory cells (regulatory T, B and NK cells) to the tumor site have been reported to support tumor growth in addition to spreading and metastasis. Every phase of tumor progression, from its initiation through metastatic expansion, is endorsed by interaction between malignant and immune cells mediated by a number of growth factors, cytokines, proteases and other molecules that modify the tumor microenvironment. Invasion and metastasis depend on intratumoral vascularization, alterations of the basement membrane and degradation of the extracellular matrix for tumor cell spreading, invasion and extravasation into the blood and lymphatic vessels. The consequent dissemination of cancerous cells to distant tissues and organs necessitates a trafficking through the vasculature, which is promoted by further interactions with cells of the immune system, including myeloid regulatory cells. Moreover, the formation of the pre-metastatic niche and specific metastasis organ tropism is also regulated and controlled by bone marrow-derived hematopoietic immune progenitor cells, immature myeloid cells and certain cytokines, chemokines and growth factors derived from tumor and immune cells, which amend the local microenvironment of the organ or tissue to promote adhesion and survival of circulating cancerous cells. Although the potential role for myeloid regulatory cells in tumor spreading and development of pre-metastatic niche has been suggested, the concept still requires further supportive experimental and clinical data, as well as data related to specific factors and mechanisms responsible for myeloid regulatory cell functioning at malignant sites. © 2014 Elsevier GmbH. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunobiology of tumor-associated MDSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protumorigenic profile of MDSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MDSCs in tumor progression and metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: BM, bone marrow; CCL2, chemokine (C-C motif) ligand 2; COX2, cyclooxygenase-2; CXCR4, C-X-C chemokine receptor type 4; DC, dendritic cells; ECM, extracellular matrix; FKBP51, FK506 binding protein 51; G-MDSCs, granulocytic MDSCs; GPCRs, G protein coupled receptors; HIF, hypoxia-inducible factor; iNOS, inducible nitric oxide synthase; MCP-1, monocyte chemoattractant protein-1; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; MMP9, matrix metalloproteinase 9; Mo-MDSCs, monocytic MDSCs; MyD88, myeloid differentiation antigen 88; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NGP, neutrophilic granule protein; NO, nitric oxide; PGE-2, prostaglandin E2; ROS, reactive oxygen species; RTKs, receptor tyrosine kinases; S1PR1, sphingosine-1-phosphate receptor 1; STAT3, signal transducer and activator of transcription 3; TLR/IL1Rs, Toll-like receptor/interleukin1 receptor family members; VCAM-1, vascular cell adhesion molecule 1. ∗ Corresponding author at: Pathology, UPMC, Scaife Hall S733, 3550 Terrace Street, Pittsburgh, PA 15261, USA. Tel.: +1 4122160727. E-mail address: [email protected] (A.A. Keskinov). http://dx.doi.org/10.1016/j.imbio.2014.07.017 0171-2985/© 2014 Elsevier GmbH. All rights reserved.

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Introduction Myeloid regulatory cells have been reported to play a key protumorigenic and immunosuppressive role in tumor development, growth and progression (Gutkin and Shurin, 2014; Zhong et al., 2014). The cells include myeloid-derived suppressor cells (MDSCs), type 2 or M2 tumor-associated macrophages, regulatory dendritic cells (DCs), type 2 or N2 tumor-associated neutrophils and a subset of mast cells. MDSCs represent a heterogenic population of mixed immature bone marrow-derived myeloid cells, including myeloid progenitors and precursors of macrophages, granulocytes and DCs. MDSCs are characterized by a combination of certain phenotypic markers and a strong ability to suppress various T cell functions (Gabrilovich and Nagaraj, 2009). In normal conditions, they usually quickly differentiate into mature granulocytes, macrophages and DCs. In contrast, in case of pathological conditions, such as cancer, infectious diseases, sepsis, trauma, bone marrow transplantation or some autoimmune disorders, a partial block in the differentiation of immature myeloid cells into mature myeloid cells results in an expansion of this population in different lymphoid and nonlymphoid tissues. MDSCs can be found in the bone marrow (BM), spleen, liver and tumor sites and have been identified in most patients and in experimental animals with cancer based on their ability to suppress T cell activation and proliferation. It has been shown that in solid tumors infiltration of MDSCs is associated with poor prognosis (Gabrilovich and Nagaraj, 2009; Marigo et al., 2008) and MDSC levels are elevated in peripheral blood of certain categories of cancer patients. For instance, Linneg CD14+HLA-DRneg monocytic MDSCs were enriched in peripheral blood of melanoma patients compared to healthy donors (Meyer et al., 2014). Circulating CD14+CD11b+HLA-DR−/low MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen-specific T cells in patients with advanced melanoma (Weide et al., 2014). Interestingly, clinical responders to ipilimumab therapy in melanoma patients showed significantly less Linneg CD14+HLA-DRneg cells as compared to non-responders, suggesting that the frequency of monocytic MDSCs may be used as predictive marker of response, as low frequencies identify patients more likely benefitting from ipilimumab treatment (Meyer et al., 2014). Characterization of peripheral CD14+HLA-DR−/low MDSC subsets in patients with non-small cell lung cancer (NSCLC) revealed that both frequency and absolute number of MDSCs were significantly increased in the peripheral blood of NSCLC patients compared with that of the healthy controls and indicated an association with metastasis, response to chemotherapy and progression-free survival (Huang et al., 2013). Cancer stage and shorter median overall survival time correlated with higher MDSC blood levels in solid tumor patients (Diaz-Montero et al., 2009; Gabitass et al., 2011; Solito et al., 2011). Another study of patients with terminal cancer investigated the overall survival time according to the numbers of granulocytic MDSCs. Patients with low levels of peripheral blood CD15+CD16low cells had significantly longer survival times than those with high levels (p = 0.0011, median survival time was 2.6 versus 0.8 months). Moreover, patients with high levels of CD15+CD16low cells tended to have poor performance status (p = 0.05) (Choi et al., 2012). Although the tumor-supporting role of tumor-associated MDSCs has been well documented, their role in the induction of pre-metastatic niche and tumor spreading is not completely understood. Immunobiology of tumor-associated MDSCs Originally described as CD11b/Gr-1 double-positive cells in mice, the Gr-1 antigens Ly-6G and Ly-6C now distinguish

G-MDSCs and Mo-MDSCs, respectively. The difference between MDSC subsets lies in morphology/phenotype and in the mechanisms by which they conduct immune function suppression (Youn and Gabrilovich, 2010). In mice, the minimum definition for the phenotype of monocytic MDSCs (Mo-MDSCs) is the co-expression of CD11b and Ly-6C, whereas granulocytic MDSCs (G-MDSCs) coexpress CD11b and Ly-6G. More recently, a number of additional markers have been associated with the MDSC phenotype (Youn et al., 2012). Phenotypically human MDSCs consist of a mixture of monocytic (expressing CD14) and granulocytic cells (expressing markers such as CD15, CD66b, CD33). Human Mo-MDSCs are mostly referred to as being CD14+ with negative or low expression of HLA-DR. Mo-MDSCs express high amounts of CD11b and CD33. Human G-MDSCs are mostly defined as CD11b+ and CD15+ or CD66b+. G-MDSCs are negative for HLA-DR, display an intermediate expression of CD33 and a variable expression of CD11b, depending on their maturation stage (Peiyuan Zhu et al., 2013). It is likely that the frequency of MDSCs subset may be different in different types of cancer (Zhang et al., 2013). For instance, patients with renal cancer display immunosuppressive CD14-CD15+CD11b+CD66b+ granulocytic MDSCs (Rodriguez et al., 2009), whereas CD14+HLA-DR2low monocytic MDSCs are found in melanoma, multiple myeloma, prostate cancer, hepatocellular carcinoma or head and neck cancer patients (Hoechst et al., 2008; Poschke et al., 2010; Serafini et al., 2006; Vuk-Pavlovic et al., 2010). Despite sharing similar phenotype and morphology MDSCs have been shown to display functional differences dependent on their location at either the primary tumor site or peripheral lymphoid organs (Corzo et al., 2010). These finding may, at least in part, be explained by differential role of adhesion molecules and cytokines in recruitment, homing and trafficking of MDSCs. The integrin adhesion molecule family is an extensive group of structurally related receptors for extracellular matrix (ECM) proteins and immunoglobulin superfamily molecules. Integrins at bone marrow-derived immune cells promote tumor inflammation by facilitating myeloid cell trafficking to the tumor microenvironment as myeloid cells express a number of functional integrins, including ␣2␤1, ␣4␤1, ␣5␤1, ␣v␤3, ␣v␤5, ␣M␤2 (CD11b) and ␣X␤2 (CD11c). Recent studies by Schmid and Varner (2012) indicate that integrin ␣4␤1, a receptor for vascular cell adhesion molecule 1 (VCAM-1) and CS-l fibronectin, selectively promotes the homing of myeloid cells to the tumor microenvironment. It is known that human and murine myeloid cells adhere to endothelial cells in vitro and to tumor endothelium in vivo via integrin ␣4␤. In fact, genetic and pharmacological blockade of integrin ␣4␤l significantly suppressed tumor inflammation, growth and metastasis. In addition, combination of anti-integrin ␣4 antibody and chemotherapeutic agents markedly reduced tumor burden compared to chemotherapeutic treatment alone (Schmid and Varner, 2012). Lechner et al. (2011) identified IL-6, IL-1␤ and GM-CSF as the major inducing factors of CD33+ MDSCs and FLT3L and TGF-␤ as major contributors to CD11b+ MDSCs development (Lechner et al., 2011). Considering the possible molecular targets of GMCSF and IL-6, the C/EBP family of transcription factors is one of particular application points. Whereas C/EBPa is the “master regulator” of the steady-state granulopoiesis, C/EBPb controls the emergency granulopoiesis induced by cytokines and infections (Hirai et al., 2006). The ablation of C/EBPb in the myeloid compartment led to a reversal of tolerance in tumor-antigen specific CD8+ T cells and revealed a full therapeutic activity of tumor-specific CTLs on established tumors. Moreover, in tumor-bearing mice, C/EBPb ablation increased the number of monocytes–macrophages and DCs with a concomitant reduction in mature granulocytes, suggesting that lack of C/EBPb might also lead to an altered

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differentiation of immature myeloid precursors (Marigo et al., 2010). Other factors associated with MDSC expansion in cancer include tumor-derived secreted factors, such as VEGF, S100A8 and S100A9, MMP9 and CCL2/MCP-1 (Gabrilovich and Nagaraj, 2009; Nagaraj et al., 2012). While CCL2, S100A8 and S100A9 recruit MDSCs to the tumor stroma, VEGF, GM-CSF, GCSF and M-CSF upregulate myelopoiesis and inhibition of myeloid cell maturation (Gabrilovich and Nagaraj, 2009; Gabrilovich et al., 2012; Sica and Bronte, 2007). Importantly, the effect of these and other factors in the tumor microenvironment on MDSCs is combinatorial and dosedependent. Furthermore, the effect might depend on the stage of MDSC differentiation. For example, Kim et al. (2012) have reported that some genes associated with an immune response and tumorpromoting function are differentially expressed in late MDSCs compared with early MDSCs (Kim et al., 2012). For example, FK506 binding protein 51 (FKBP51) was increased in late MDSCs and, thus, FKBP51 knockdown reduced suppression of T cell proliferation mediated by the MDSC. Immune response-related genes, including cell surface molecules, cytokines, chemokines and cell signaling molecules are down-regulated in both Mo-MDSCs and G-MDSCs at the late time point, suggesting that the antigen-presenting function of MDSCs might decrease with tumor growth. In contrast, some genes related to MDSC immunosuppressive function, such as S100a8 and S100a9 in Mo-MDSCs and urokinase (Plau) in G-MDSCs, are increased with tumor growth. In addition, iron-binding protein – lipocalin 2 (Lcn2), noted for promoting tumor metastasis, and leukotriene A4 hydrolase (Lta4h), which is involved in leukotriene B4-mediated MDSC chemoattraction were also increased in Mo-MDSCs and G-MDSCs, respectively, at a late time point (Kim et al., 2012). Finally, apoptosis-related factors, such as NLR family apoptosis inhibitory protein 2 and the proliferation-related factor Ki67, were also overexpressed in GMDSCs at the late time point, suggesting that G-MDSCs might be dividing rapidly and be resistant to cell death. This finding may explain why G-MDSCs become such a large population at the late time point during tumor growth (Kim et al., 2012). Tumor-derived exosomes can modulate myeloid cells in the tumor microenvironment and distantly at hematopoietic organs and pre-metastatic sites. It is shown that they alter myelopoiesis and lead to abnormal differentiation of myeloid cells in favor of MDSCs (Sevko and Umansky, 2013). Exosomes impair the capacity of bone marrow derived CD11b+ myeloid cells and CD14+ monocytes to differentiate into functional DCs, leading to negative effects on antitumor immune responses. Exosomes can induce the accumulation of MDSCs, which markedly increases production of inflammatory cytokines, including IL-6 and VEGF, and promotes tumor growth. They also demonstrated that tumor microenvironmental factors producing exosomal prostaglandin E2 (PGE-2) and TGF-␤ were enriched or increased as the tumor progress (Xiang et al., 2009). Specific role of adaptor protein myeloid differentiation antigen 88 (MyD88) for tumor exosome-mediated expansion of MDSCs has been also shown (Chalmin et al., 2010; Liu et al., 2010). PGE2 and cyclooxygenase-2 (COX2) are produced by many tumors and are major contributors to the inflammatory milieu. Thus elevated PGE2 levels are associated with higher levels and more suppressive MDSCs as COX2 is a key factor in the activation of MDSCs. It regulates the expression of arginase 1, iNOS and PGE2 (Taketo, 1998). Obermajer et al. (2011a,b) have demonstrated that it induces and stabilizes the expression of CXCR4 on cancerassociated MDSCs and leads to CXCL12/SDF1-driven accumulation of MDSCs (Obermajer et al., 2011a,b). MDSCs express high levels of COX2 and are a major source of PGE2 secretion in human cancers (Obermajer et al., 2011a,b). It has been speculated that the positive feedback between PGE2 and COX2 redirects the differentiation of

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human DCs toward stable MDSCs (Serafini, 2010). The resulting positive feedback loop between PGE2 and COX2 is essential for the functional stability of MDSCs, their ability to produce the additional MDSC-associated suppressive mediators and to suppress CD8+ T cell function (Obermajer et al., 2011a,b).

Protumorigenic profile of MDSCs At least four major mechanisms suggested for MDSCs are associated with the suppression of immune cells functioning: depletion of amino acids required by lymphocytes, oxidative stress induced by production of ROS and reactive nitrogen species, interference with lymphocyte trafficking and viability and activation and expansion of regulatory T (Treg) cells (Gabrilovich et al., 2012). Numerous findings also suggest that the monocytic and granulocytic MDSC subpopulations exhibit distinct immunosuppressive functions. Granulocytic MDSCs are the prevalent population in the tissues and circulation in tumor-bearing mice, but are individually less immunosuppressive than monocytic MDSCs. Granulocytic MDSCs are closely linked to CD8+ T cell suppression through the production of reactive oxygen species (ROS). In contrast, monocytic MDSCs suppress lymphocyte activation through the activity of enzymes arginase 1(ARG1), inducible nitric oxide synthase (iNOS) and ROS. Murine MDSCs use two enzymes involved in l-arginine metabolism to control T cell responses: arginase 1 (ARG1), which depletes the milieu of l-arginine, and iNOS2, which generates nitric oxide (NO). L-arginine is essential for T cells to regulate the optimal use of IL-2 and to develop a T cell memory phenotype. Thus, depletion of arginine by MDSCs suppresses CD4+ and CD8+ T cell activation. While IFN-␥ and TNF-␣ in the tumor microenvironment induce iNOS in MDSCs, releasing NO, which blocks the phosphorylation and activation of several targets in the IL-2 receptor signaling pathway and induces T cell apoptosis. Cysteine is another essential amino acid, which T cells are unable to synthesize or import intracellularly. This amino acid is crucial for T cell activation. In regular immune responses, DCs and macrophages synthesize cysteine from methionine and import extracellular cystine for cysteine conversion, which afterwards is delivered to T cells by antigen-presenting cells during antigen presentation. Additionally, DCs and macrophages secrete thioredoxin, which converts extracellular cystine to cysteine, which is also available for up-take by T cells (Angelini et al., 2002; Castellani et al., 2008). Myeloid cells are also dependent on importing cystine for conversion to cysteine. Thus, in the tumor microenvironment, MDSCs uptake most of the available cystine, depriving DCs and macrophages. Since MDSCs do not export cysteine, they deprive T cells of it (Srivastava et al., 2010). MDSCs use different mechanisms to affect the viability, proliferation, effector functions and migration of T cells (Gabrilovich et al., 2012). For instance, MDSCs down-regulate l-selectin (CD62L) on naive T cells, which reduce the T cell capacity to migrate to lymph nodes. It has been demonstrated that T cell reduction of l-selectin level, commonly seen in individuals with cancer, inversely correlates with MDSC levels (Hanson et al., 2009). MDSCs also affect tumor immunity by polarizing T cells toward a tumor-promoting type 2 phenotype, by producing IL-10 and down-regulating macrophage production of IL-12 (Sinha et al., 2007). MDSCs may also impair NK cells by inhibiting their cytotoxicity ability and IFN-␥ production (Li et al., 2009; Liu et al., 2007). MDSCs may modulate cytokine production of macrophages, skewing them toward decreased production of IL-12, potentially through Toll-like receptor 4 signaling (Bunt et al., 2009). Eruslanov et al. (2012) found that MDSCs from cancer patients produced substantially more pro-inflammatory chemokines and cytokines,

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Acvaon and expansion of regulatory T (Treg) cells

MDSC

Interference with lymphocyte trafficking and viability

Immunosuppression, immune tolerance in cancer

Inhibion of NK cell acvity

Oxidave stress induced by producon of ROS and RNS Inhibion of angen presentaon by DC

Depleon of Arginine & Cysteine in the tumor microenvironment

Differenaon into regulatory DC

Producon of immunosuppressive cytokines

Fig. 1. Several major mechanisms suggested for MDSC-mediated suppression of immune cells functioning: depletion of amino acids essential for lymphocyte functioning (arginine, cysteine), production of ROS and reactive nitrogen species which leads to nitration/nitrosylation of TCR and CD8 molecules on the surface of T cells, interference with lymphocyte trafficking and viability via downregulation of lselectin (CD62L) on naive T cells, activation and expansion of regulatory T (Treg) cells through production of IL-10 and TGF-␤. Overall MDSC expansion and IL-10 production inhibit dendritic cell (DC) antigen presentation. MDSCs may be reprogrammed by the tumor microenvironment into regulatory DCs (regDCs). MDSCs suppress natural killer (NK) cell cytotoxicity and NK interferon gamma (IFN-␥) production.

aggravating the tumor microenvironment toward malignant development. Granulocytic CD15highCD33low cells overproduced CCL2, CCL3, CCL4 and G-CSF; Monocyte-type CD15low CD33high myeloid cells secreted elevated amounts of chemokines and cytokines, including CCL2, CCL3, CCL4␤, IL-6 and IL-8 (Fig. 1). One of the major characteristics of all activated myeloid cells is the production of ROS and reactive nitrogen species. Lu et al. has demonstrated that MDSCs induced T cell tolerance via production of free radical peroxynitrite (PNT) and nitration/nitrosylation of TCR and CD8 molecules on the surface of T cells, which results in the lost the ability of T cells to recognize antigenic peptide/MHC complexes and perform their antitumor activity (Lu et al., 2011). Importantly, MDSCs can impair T cell activation by directly inducing Tregs through the production of IL-10 and TGF-␤, or arginase, which is independent of TGF-␤ (Gabrilovich and Nagaraj, 2009). MDSCs can be reprogrammed by the tumor microenvironment into a tolerogenic state, becoming regulatory DCs (regDCs) (Zhong et al., 2014). Overall MDSC expansion and IL-10 production inhibit dendritic cell antigen presentation (Srivastava et al., 2012). MDSCs in tumor progression and metastasis Cancer metastasis dominates among the most life-threatening aspect of the disease, accounting for approximately 90% of human cancer related deaths. Tumor stroma, consisting primary of connective tissue and extracellular matrix (ECM), vasculature, fibroblasts and an infiltrate of immune cells, is critical for tumor growth. Apart from providing the growing tumor with structure and blood supply, stromal cells are part of a paracrine loop necessary for the survival of cancerous cells and also induction of immune suppression (Engels et al., 2012). Recent evidence suggests the primary tumor itself can influence and alter the environment of secondary organs by promoting the formation of supportive metastatic microenvironments, termed pre-metastatic niches, prior to tumor cell dissemination. The organotropism observed in different tumor types is largely determined

and driven by the tumor-derived factors secreted from the primary tumor and its stroma (Smith and Kang, 2013). The formation of metastasis is a complex and sequential process, involving several basic steps (Gupta and Massague, 2006; Li et al., 2013): departure from the primary tumor, survival in the circulatory system, breaching of endothelium and basement membrane of target organs and establishment of a colony of metastatic cells. Four major routes are considered to be principal in the spreading of tumor cells: lymphatic vessels, blood vessels, serosal surfaces and tumor growth along nerve fibers (Bacac and Stamenkovic, 2008; Marchesi et al., 2010). Metastatic progression is strongly associated with hypoxia within the primary tumor. Hypoxia-inducible factor (HIF)-1␣ is the main downstream regulator of the hypoxic response in tumor cells. Elevated HIF-1␣ expression is reported to correlate with increased tumor stage and poor prognosis in a variety of cancer types (Joyce and Pollard, 2009; Semenza, 2012). Therefore it is important for formation of pre-metastatic niches mainly through the hypoxia-induced production of lysyl oxidase (Erler et al., 2009). A common point amongst different models of the pre-metastatic niche is the mobilization of myeloid cell lineages from the bone marrow and recruitment to specific pre-metastatic sites (Sceneay et al., 2013). Deng et al. showed that S1PR1-STAT3 up-regulation in tumor cells induces factors that activate S1PR1-STAT3 in various cells in pre-metastatic sites, leading to pre-metastatic niche formation. Moreover, persistent activation of STAT3 occurs in distant organs before tumor cell arrival. Stat3 or S1pr1 ablation in myeloid cells also abrogated STAT3 activity in the entire future metastatic site, further suggesting an important role of myeloid cells in establishing pre-metastatic niches (Deng et al., 2012). Persistent activation of STAT3 in myeloid progenitors prevents their differentiation into mature cells and together with the induction of proliferation favors their continuous presence in tumor microenvironments (Dilek et al., 2012; Gabrilovich and Nagaraj, 2009). Inflammatory factors released by tissues activate G protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) or Tolllike receptor/interleukin1 receptor family members (TLR/IL1Rs), which initiate myeloid cell recruitment during inflammation (Ley et al., 2007). By cell depletion studies, it was determined that the G-CSF-tumor effect was largely due to the induced granulocytic MDSC response (Abrams and Waight, 2012). Initiation of metastasis involves intravasation of tumor stromal cells, including myeloid cells, from primary tumor sites (Fidler, 2003). Activation of Toll-like receptors, specifically TLR2, on myeloid cells by tumor-produced factors has been shown to create an inflammatory milieu that mediates distant-site metastasis (Kim et al., 2009). Two main MDSC-mediated mechanisms are involved in promoting metastasis: enhancement of tumor-derived metastatic cells migration from primary site of carcinogenesis and pre-metastatic niche formation. The latter is crucial for determining whether a disseminated tumor cell survives and proliferates, becomes quiescent, or dies at metastatic sites (Joyce and Pollard, 2009). At early stages CD11b+Gr-1+ cells can induce mesenchymal transition (Toh et al., 2011) and in later stages they have been shown to degrade the ECM at the invasive front, facilitating tumor cell invasion and metastasis (Brandau et al., 2013; Engels et al., 2012; Yang and Weinberg, 2008). Degradation of ECM leads to the mobilization of growth factors and facilitates the migration of vascular cells into new environments (Huang et al., 2002). For instance, Yang et al. (2004) found that MDSCs infiltrate into tumors and promote expressing high levels of matrix metalloproteinase 9 (MMP9). Moreover, MDSCs have the ability to incorporate directly into tumor endothelium. MDSC-derived MMP9 was shown to increase the bioavailability of VEGF in tumors and promote tumor angiogenesis and vascular stability. Accordingly, selective deletion of MMP9 in MDSC completely abolished their tumor-promoting activity (Yang et al., 2004). Moreover, Ly6G+Ly6Clow granulocytic subset

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of CD11+/Gr-1+ myeloid cells, mobilized from the bone marrow by tumor-derived G-CSF, secrete MMP9, S100A8 and S100A9, as well as the chemoattractant protein Bv8 (also known as prokineticin 2, or Prok2) to enhance migration and homing of tumor cells (Kowanetz et al., 2010). Bv8 stimulates the production of granulocytic and monocytic colonies in vitro and mobilizes hematopoietic cells such as CD11b+Gr1+ cells to the blood (LeCouter et al., 2004). Anti-Bv8 treatment of mice implanted with human tumors resulted in reduction of CD11b+ Gr1+ mobilization from the bone marrow causing decrease in tumor growth and neoangiogenesis. Within the tumor microenvironment MDSCs express receptors for S100A8/A9 and upregulate the levels of S100A8/A9 via an autocrine loop (Ostrand-Rosenberg, 2008). S100 proteins have been implicated in both priming of the metastatic organ and promotion of metastatic spread (Hiratsuka et al., 2006; Ichikawa et al., 2011). S100A8/A9 heterodimers mediate these effects through at least two mechanisms: they block the differentiation of myeloid precursors to differentiated DCs/macrophages through a STAT3dependent mechanism, and by chemoattracting MDSCs into the tumor through a NF-kB-dependent pathway (Cheng et al., 2008; Sinha et al., 2008). The MDSC up-regulation of proteases is not the only process contributing to the tumor metastasis promotion. Boutte et al. has demonstrated the importance of neutrophilic granule protein (NGP, a cathepsin B inhibitor) that is down-regulated in MDSC from metastatic tumor-bearing mice compared with non-metastatic controls. Up-regulation of NGP in tumors delayed primary tumor growth and greatly reduced tumor vasculature, invasiveness and metastasis (Boutte et al., 2011). Pre-metastatic niches are supportive microenvironments established in secondary organs by primary neoplastic lesions prior to tumor cell dissemination. The pre-metastatic niche promoting functions of myeloid cells has been attributed to their integrin expression and production of various chemokines, growth factors, angiogenic factors and inflammatory mediators in response to tumor/stroma derived factors (Psaila and Lyden, 2009). Yan et al. (2010) described CD11b+Gr-1+ cells to be able for preparing the pre-metastatic niche promoting tumor cell dissemination (Yan et al., 2010). Secretion of versican from CD11b+Gr-1+Ly6Chigh myeloid cells pushes disseminating tumor cells from a mesenchymal to epithelial phenotype to promote metastatic colonization of the pre-metastatic niche (Gao et al., 2012). Additionally, tumorsecreted versican activates CD11b+Gr-1+ myeloid cells to produce TNF-␣, which in turn enhances cancer cell survival while recruiting leukocytes to create a proinflammatory pre-metastatic niche (Kim et al., 2009). As well as promoting vascular remodeling and a proinflammatory environment through the secretion of factors such as MMP9, CD11b+Gr-1+ myeloid cells can also suppress the immune response in the pre-metastatic niche through reduction of IFN-␥ (Yan et al., 2010). CD11b+Ly6G+Ly6C med granulocytic myeloid cells mobilized from the bone marrow by hypoxic tumor cell-derived MCP-1 (mentioned above as CCL2) help to create an immunosuppressive pre-metastatic niche through suppression of NK cell cytotoxicity and maturity (Sceneay et al., 2012). Interestingly, murine CD11b+Ly6G+ myeloid cells that differentiate into tumor-entrained neutrophils at the primary site prevent pre-metastatic niche formation through targeted cytotoxicity of tumor cells in pre-metastatic organs (Granot et al., 2011). In contrast, enhanced STAT3 signaling in CD11b+ myeloid cells at the primary tumor site, mediated by tumor-derived factors from STAT3-activated tumor cells, promotes the invasion, survival and accumulation of these myeloid cells, which drive pre-metastatic niche formation (Deng et al., 2012). Metastasizing cancer cells induce higher MDSCs infiltration alongside with exaggerated IL6 secretion. These factors triggered a persistent increase of pSTAT3 in tumor cells. This potential tumor–MDSC axis involving IL-6

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trans-signaling directly affected cancer cell aggressiveness, leading to spontaneous metastasis (Oh and Gu, 2013). Conclusions Interactions of malignant cells with different elements of the microenvironment, especially those of bone-marrow-derived myeloid regulatory cells, are important in various aspects of tumor spreading and metastasis. Comprising a heterogenic population of immature myeloid cells, MDSCs are now in the scope of profound research as they have been suggested to constitute tumor-favoring microenvironments. Accumulating evidence has demonstrated MDSCs, a heterogeneous population of cells, play an important role in the subversion, inhibition, and down-regulation of the immune response to cancer. However, the characteristics of these cells in the pre-metastatic niche formation, particularly clinical relevance, in different cancers remain unclear. A better understanding of MDSC biology can benefit by introducing new therapeutic options and improving outcome results in clinical oncology. As metastatic disease is the biggest problem in modern oncology, targeting the ability of myeloid regulatory cells, including MDSCs, to support tumor spreading and formation of pre-metastatic niche should provide a new and important tool for cancer treatment. References Abrams, S.I., Waight, J.D., 2012. Identification of a G-CSF-granulocytic MDSC axis that promotes tumor progression. Oncoimmunology 1, 550. Angelini, G., Gardella, S., Ardy, M., Ciriolo, M.R., Filomeni, G., Di Trapani, G., Clarke, F., Sitia, R., Rubartelli, A., 2002. Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. Proc. Natl. Acad. Sci. U. S. A. 99, 1491. Bacac, M., Stamenkovic, I., 2008. Metastatic cancer cell. Annu. Rev. Pathol. 3, 221. Boutte, A.M., Friedman, D.B., Bogyo, M., Min, Y., Yang, L., Lin, P.C., 2011. Identification of a myeloid-derived suppressor cell cystatin-like protein that inhibits metastasis. FASEB J. 25, 2626. Brandau, S., Moses, K., Lang, S., 2013. The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins? Semin. Cancer Biol. 23, 171. Bunt, S.K., Clements, V.K., Hanson, E.M., Sinha, P., Ostrand-Rosenberg, S., 2009. Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4. J. Leukoc. Biol. 85, 996. Castellani, P., Angelini, G., Delfino, L., Matucci, A., Rubartelli, A., 2008. The thiol redox state of lymphoid organs is modified by immunization: role of different immune cell populations. Eur. J. Immunol. 38, 2419. Chalmin, F., Ladoire, S., Mignot, G., Vincent, J., Bruchard, M., Remy-Martin, J.P., Boireau, W., Rouleau, A., Simon, B., Lanneau, D., De Thonel, A., Multhoff, G., Hamman, A., Martin, F., Chauffert, B., Solary, E., Zitvogel, L., Garrido, C., Ryffel, B., Borg, C., Apetoh, L., Rebe, C., Ghiringhelli, F., 2010. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J. Clin. Invest. 120, 457. Cheng, P., Corzo, C.A., Luetteke, N., Yu, B., Nagaraj, S., Bui, M.M., Ortiz, M., Nacken, W., Sorg, C., Vogl, T., Roth, J., Gabrilovich, D.I., 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. Choi, J., Suh, B., Ahn, Y.-O., Kim, T.M., Lee, J.-O., Lee, S.-H., Heo, D.S., 2012. CD15+/CD16low human granulocytes from terminal cancer patients: granulocytic myeloid-derived suppressor cells that have suppressive function. Tumour Biol. 33, 121. Corzo, C.A., Condamine, T., Lu, L., Cotter, M.J., Youn, J.I., Cheng, P., Cho, H.I., Celis, E., Quiceno, D.G., Padhya, T., McCaffrey, T.V., McCaffrey, J.C., Gabrilovich, D.I., 2010. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207, 2439. Deng, J., Liu, Y., Lee, H., Herrmann, A., Zhang, W., Zhang, C., Shen, S., Priceman, S.J., Kujawski, M., Pal, S.K., Raubitschek, A., Hoon, D.S., Forman, S., Figlin, R.A., Liu, J., Jove, R., Yu, H., 2012. S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer Cell 21, 642. Diaz-Montero, C.M., Salem, M.L., Nishimura, M.I., Garrett-Mayer, E., Cole, D.J., Montero, A.J., 2009. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicincyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58, 49. Dilek, N., Vuillefroy de Silly, R., Blancho, G., Vanhove, B., 2012. Myeloid-derived suppressor cells: mechanisms of action and recent advances in their role in transplant tolerance. Front. Immunol. 3, 208. Engels, B., Rowley, D.A., Schreiber, H., 2012. Targeting stroma to treat cancers. Semin. Cancer Biol. 22, 41.

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