Chemokines and their receptors promoting the recruitment of myeloid-derived suppressor cells into the tumor

Molecular Immunology 117 (2020) 201–215

Contents lists available at ScienceDirect

Molecular Immunology journal homepage: www.elsevier.com/locate/molimm

Review

Chemokines and their receptors promoting the recruitment of myeloidderived suppressor cells into the tumor

T

Bao-Hua Lia,b, Malgorzata A. Garstkaa,b,c, Zong-Fang Lib,d,* a

Core Research Laboratory, Xi'an, 710004, Shaanxi, China National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Xi'an, 710004, Shaanxi, China c Department of Endocrinology, Xi'an, 710004, Shaanxi, China d Department of General Surgery, The Second Affiliated Hospital, College of Medicine, Jiaotong University, Xi'an, 710004, Shaanxi, China b

A R T I C LE I N FO

A B S T R A C T

Keywords: MDSCs Chemo-attractant cytokines Tumor microenvironment Immunosuppression Therapeutic targeting Cancer immunotherapy

Myeloid-derived suppressor cells (MDSCs) expand in tumor-bearing host. They suppress anti-tumor immune response and promote tumor growth. Chemokines play a vital role in recruiting MDSCs into tumor tissue. They can also induce the generation of MDSCs in the bone marrow, maintain their suppressive activity, and promote their proliferation and differentiation. Here, we review CCL2/CCL12-CCR2, CCL3/4/5-CCR5, CCL15-CCR1, CX3CL1/CCL26-CX3CR1, CXCL5/2/1-CXCR2, CXCL8-CXCR1/2, CCL21-CCR7, CXCL13-CXCR5 signaling pathways, their role in MDSCs recruitment to tumor tissue, and their correlation with tumor development, metastasis and prognosis. Targeting chemokines and their receptors may serve as a promising strategy in immunotherapy, especially combined with other strategies such as chemotherapy, cyclin-dependent kinase or immune checkpoints inhibitors.

1. Introduction Tumors are characterized by immunosuppressive microenvironment that inhibits anti-tumor immune response and promotes tumor growth and metastasis. In recent years, myeloid-derived suppressor cells (MDSCs) have received a lot of attention as the major inhibitors of antitumor immune response and factors limiting the effects of cancer immunotherapy. MDSCs are heterogenous. They are myeloid origin, consisting of myeloid progenitor cells, immature macrophages (Mφs), immature granulocytes and immature dendritic cells (DCs). Under pathological conditions, they are expanded compared with normal conditions. They have typical phenotypes and potent immune suppressive activities (Gabrilovich, 2017; Gabrilovich and Nagaraj, 2009; Umansky et al., 2016). MDSCs produce various immune suppressive factors, including arginase I, inducible nitric oxide synthase, and reactive oxygen species (ROS) in the form of superoxide anion (O2−), hydrogen peroxide (H2O2), and peroxynitrite (PNT) (ONOO−). MDSCs can suppress the immune responses of T cells, inhibit the function of natural killer (NK) cells, induce the production of regulatory T cells, and control the

cytokine production by Mφs (Gabrilovich, 2017; Gabrilovich and Nagaraj, 2009; Schrader, 2013; Serafini et al., 2004; Talmadge and Gabrilovich, 2013; Viktor Umansky et al., 2016). In addition, MDSCs can promote epithelial-mesenchymal transition and facilitate tumor angiogenesis and metastasis (Gabrilovich, 2017; Schrader, 2013; Toh et al., 2011; Umansky et al., 2016). MDSCs can be divided into two subtypes, polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs), they have different markers and morphologies. PMN-MDSCs are similar to neutrophils and M-MDSCs are similar to monocytes. In mice, Gr1+CD11b+ is the marker of total MDSC, CD11b+Ly6G+Ly6Clo is for PMN-MDSC and CD11b+Ly6G−Ly6Chi is for M-MDSC (Bronte et al., 2016; Gabrilovich, 2017). In human, Bronte and Gabrilovich defined CD11b+CD14−CD15+ (or CD66b+) as PMN-MDSC, CD11b+CD14+CD15−HLA-DR-/lo as M-MDSC (Bronte et al., 2016); while Umansky defined Lin−HLA-DR-/loCD33+CD11b+CD14−CD15+ or Lin−HLA-DR-/loCD33+ as PMN-MDSC and Lin−HLA-DR-/lo CD11b+CD14+CD15− or HLA-DR-/loCD14+ as M-MDSC (Umansky et al., 2016). These two subtypes suppress antigen-specific T cell responses via different effector molecules and signaling pathways. PMN-

Abbreviations: DC, dendritic cell; HCC, hepatocellular carcinoma; HIF, hypoxia-inducible factor; LLC, Lewis lung carcinoma; MDSC, myeloid-derived suppressor cell; M-MDSCs, monocytic MDSCs; Mϕs, macrophages; NK, natural killer; PMN-MDSCs, polymorphonuclear MDSCs; ROS, reactive oxygen species; TB, tumor-bearing ⁎ Corresponding author at: Department of General Surgery, The Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, Shaanxi, 710004, China. E-mail address: [email protected] (Z.-F. Li). https://doi.org/10.1016/j.molimm.2019.11.014 Received 21 June 2019; Received in revised form 27 November 2019; Accepted 30 November 2019 0161-5890/ © 2019 Elsevier Ltd. All rights reserved.

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

MDSCs produce large amounts of ROS (O2-, H2O2, and PNT). Because ROS are very unstable and only active for a short time, PMN-MDSCs need close cell-to-cell contact to inhibit T cells. PMN-MDSCs suppress Tcell-mediated responses primarily in an antigen-specific manner via increased activity of signal transducer and activator of transcription 3 (STAT3) and nicotinamide adenine dinucleotide phosphate (NADPH) signaling pathways. M-MDSCs produce high amounts of NO, Arg1 and immune-suppressive cytokines, including IL-10 and TGF-β. These molecules are longer-lived than ROS, and M-MDSCs do not need close contact with T cells. Thus, M-MDSCs suppress T-cell responses both in antigen-specific and non-specific manners via STAT1 and inducible nitric oxide synthase signaling pathways and possess more potent suppressive abilities than PMN-MDSCs (Gabrilovich, 2017; Kumar et al., 2016). In the peripheral lymphoid organs, MDSCs exert suppressive properties via various mechanisms: inos-induced NO production, noxmediated ROS generation, and the depletion of crucial nutrients for T cells: L-arginine (through Arg1), L-cysteine and tryptophan (IDOmediated). The inflammatory and hypoxic tumor microenvironment induces HIF-1α-mediated increase in Arg1 and inos expression and decrease in ROS production by MDSCs, upregulation of PD-L1 on MDSC surface, and secretion of CCL4 and CCL5 chemokines. Such changes in the tumor microenvironment produce more potent immunosuppressive functions of MDSCs in the tumor (Dmitry I. Gabrilovich, 2017; Gabrilovich and Nagaraj, 2009; Kumar et al., 2016). Increased numbers of MDSCs present in tumor-bearing (TB) mice and cancer patients cause the dysfunction of anti-cancer immune response, and correlate with shorter survival in patients with various cancers (Cui et al., 2013; De Sanctis et al., 2016; Filipazzi et al., 2012; Parker et al., 2015; Poschke and Kiessling, 2012; Umansky and Sevko, 2012; Wang et al., 2013; Weide et al., 2014). MDSCs accumulation in tumor tissue can be induced by various factors, including chemokines, cytokines, and complements, produced by tumor and normal host cells (De Sanctis et al., 2016; Gabrilovich et al., 2012; Kumar et al., 2016; Ostrand-Rosenberg and Sinha, 2009; Umansky et al., 2016). Amongst these, chemokines as key mediators of the chemotactic cell recruitment have been extensively studied in many tumor models and cancer patients. Chemokines are chemotactic cytokines with a molecular weight of 7−12 kDa that control the migration of immune cells. There are more than 50 chemokine ligands in humans and mice. They are classified into four subfamilies - CXC, CC, C, and CX3C - based on the position of their first two cysteine residues. To date, 20 chemokine receptors have been described. The binding of chemokine to its specific receptor mediates cell migration and adhesion (Chow and Luster, 2014; Marcuzzi et al., 2018). Here, we review the chemokines and their receptors, including CCL2/CCL12-CCR2, CCL3/4/5-CCR5, CCL15-CCR1, CX3CL1/CCL26CX3CR1, CXCL5/2/1-CXCR2, CXCL8-CXCR1/2, CCL21-CCR7, CXCL13CXCR5 axes important for MDSCs recruitment to tumor site. We present the current understanding of the underlying mechanisms and discuss the implications of these findings for therapeutic targeting of MDSCs.

2007; Lehmann et al., 2016; Ninomiya et al., 2015). The expression of CCL2 was elevated in many animal tumor models and cancer patients, including glioblastoma, prostate, breast, ovarian, gastric, esophageal, non-small-cell lung, HCC carcinomas, melanoma and renal cell carcinoma (Arenberg et al., 2000; Bottazzi et al., 1990; Conti and Rollins, 2004; Eisenblaetter et al., 2017; Guan et al., 2018; Huang et al., 2007; Izhak et al., 2010). It correlated with high tumor grade, reduced overall survival in patients, and might serve as an important prognostic factor for survival (Chang et al., 2016; Chavey et al., 2007; Ueno et al., 2000). In murine glioma, CCL2 produced by microglia, recruited CCR2+Ly6C+ monocytic MDSCs (M-MDSCs) to the tumor site, while CCL2-deficient mice had significantly reduced MDSCs infiltration into the tumor (Chang et al., 2016). In renal tumor, CCL2 produced at high levels by tumor-associated Mφs induced recruitment of M-MDSCs and PMN-MDSCs into the tumor (Hale et al., 2015). In irradiated MC38 colon tumors and LLC tumor model, evoked activation of stimulator of interferon genes STING induced expression of CCL2, CCL7, CCL12 in the tumor, which mobilized CCR2-positive M-MDSCs into the tumor and resulted in radio-resistance. Knocking out or blocking CCR2 reversed radio-resistance and improved anti-tumor efficacy in irradiated TB mice (Liang et al., 2017). In lung cancer model, TRAIL-resistant tumors exhibited higher CCL2 expression and promoted CCR2-dependent accumulation of MDSCs into the tumor (Hartwig et al., 2017). In human and mouse colorectal cancer, the expression of CCL2 and accumulation of MDSCs in the colon increased with neoplastic progression. CCL2 enhanced PMN-MDSC-mediated suppression of T cells via ROS production and decrease in T cell receptor ς chain (Chun et al., 2015). CCL2-CCR2 signaling mediated MDSC recruitment to tumor tissues also in melanoma and HCC (Huang et al., 2007; Lesokhin et al., 2012). Pivotal role of CCL2 in MDSCs recruitment and cancer progression make it a potential target in anti-cancer therapy. Blocking the CCL2 using soluble CCR2 fragment or neutralizing antibody, solo or in combination with chemotherapeutic drug docetaxel, demonstrated significant therapeutic effects (Kirk et al., 2013). Inhibition of CCR2 with neutralizing or blocking antibody significantly decreased the accumulation of MDSCs in the tumor, indicating that CCL2-CCR2 signaling may contribute to MDSCs migration and accumulation in tumor tissue. CCL12, chemokine (C-C motif) ligand 12, also known as monocyte chemotactic protein 5 (MCP-5), is mainly produced by Mφs and astrocytes. It can attract eosinophils, monocytes and lymphocytes (DeLeon-Pennell et al., 2017; Mojsilovic-Petrovic et al., 2007). In irradiated MC38 colon tumors and LLC tumor model, high CCL12 levels resulted in the recruitment of CCR2-positive M-MDSCs into the tumor (Liang et al., 2017). In the premetastatic lungs of mice with B16F10, HEK-293 T, and MS1 tumor cells implants, CCL12-dependent increase in the number of M-MDSCs correlated with enhanced tumor cell arrest and metastasis. Knockdown of CCL12 using RNA interference in TB mice decreased the number of M-MDSCs in the premetastatic lungs, and attenuated tumor metastasis (Shi et al., 2017). However, authors did not investigate whether observed effect was CCR2-dependent. CCL2 role in recruitment of MDSCs and cancer progression is well established. CCL2 could be a potential target in anti-cancer treatment solo, or in combination therapy. The involvement of CCL12 in MDSCs accumulation in tumor tissue requires further study.

2. CCL2/CCL12-CCR2 signaling plays a pivotal role in MDSCs migration CCL2, chemokine (CC motif) ligand 2, also known as monocyte chemotactic protein-1 (MCP-1), is primarily secreted by Mφs, monocytes, DCs, astrocytes, microglia, endothelial cells, keratinocytes, mesangial cells, smooth muscle cells, fibroblasts, osteoblasts, neurons. It can also be produced by tumors, including prostate cancer, breast cancer, colorectal cancer, malignant glioma, malignant fibrous histiocytoma, and Lewis lung carcinoma (LLC) (Lim et al., 2016; Vakilian et al., 2017; Yoshimura, 2017, 2018). CCL2 is a high affinity ligand for the chemokine receptor CCR2 found on the cell membrane of basophils, monocytes, DCs, Mφs, NK cells, memory T cells, and MDSCs (Behfar et al., 2017; Bronte and Pittet, 2013; Hale et al., 2015; Huang et al.,

3. Tumor-derived and hematopoietic CCR5 ligands induce the generation, migration, proliferation of MDSCs and maintain their suppressive activity CCR5 ligands include CCL3, CCL4 and CCL5. CCL3, chemokine (C-C motif) ligand 3 (CCL3), also known as macrophage inflammatory protein 1-alpha (MIP-1-α), is produced by neutrophils, Mφs, monocytes, 202

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

immature DCs, NK cells, T cells, B cells, platelets, fibroblasts, epithelial cells and some tumor cells including leukemia cells, and multiple myelomalymphoblastoid cell lines. CCL3 can attract Mφs, monocytes, neutrophils, immature DCs, T cells and NK cells (Baba and Mukaida, 2014; Choi et al., 2000; Menten et al., 2002). CCL4, also known as macrophage inflammatory protein-1β (MIP-1β), can be produced by neutrophils, monocytes, DCs, NK cells, B cells, T cells, fibroblasts, endothelial, epithelial cells, and astrocytoma cells. It is a chemoattractant for Mφs, monocytes, immature DCs, T cells, and NK cells (T. T. Chang and Chen, 2016; Menten et al., 2002). CCL5, also known as RANTES (regulated on activation, normal T cell expressed and secreted), is expressed by T lymphocytes, eosinophils, Mφs, platelets, fibroblasts, endothelial, epithelial cells, and some tumors, including melanoma, prostate cancer, and pancreatic ductal carcinoma. It can attract T cells, monocytes, basophils, eosinophils, NK cells, DCs, and mast cells (Appay and Rowland-Jones, 2001; Levy, 2009; Monti et al., 2004; Mrowietz et al., 1999; Vaday et al., 2006). Tumor-derived CCL5 was detected in many clinical specimens of breast and cervical cancers. The levels of CCL5 were positively correlated with tumor stage, relapse and metastasis (Niwa et al., 2001; Sauer et al., 2008; Soria and Ben-Baruch, 2008; Yaal-Hahoshen et al., 2006). In melanoma mice and patients, elevated levels of CCR5 ligands (CCL3, CCL4, CCL5) coincided with CCR5+MDSCs accumulation in melanoma lesions and tumor progression. These CCR5+MDSCs exhibited a stronger suppressive activity (Blattner et al., 2018). Blocking CCR5/ CCR5 ligands interaction (using mCCR5-Ig fusion protein, anti-CCR5 antibody, or CCL5-neutralizing mAb) reduced the number and the immunosuppressive potential of tumor-infiltrating MDSCs, inhibited metastasis, improved the survival of tumor-bearing mice, and enhanced the efficacy of anti-PD1 cancer treatment (Blattner et al., 2018; Tang et al., 2015; Yang et al., 2018; Zhang et al., 2013). In TRAMP-C1 prostate tumors, CCL5 ligands (CCL3, CCL4, CCL5) played a pivotal role in the generation of MDSCs in bone marrow. They induced the proliferation of PMN-MDSCs in the bone marrow, and CCR5-dependent mobilization of PMN-MDSCs from the bone marrow to the blood (Hawila et al., 2017). In orthotopic and spontaneous mammary tumors, CCL5 deficiency negatively altered the morphology, differentiation, and immunosuppressive activity of MDSCs, and reduced tumor growth (Zhang et al., 2013). CCR5 ligands not only attract MDSCs to the tumor site, but also induce MDSCs generation and proliferation in the bone marrow. Targeting CCR5/CCR5 ligands axes could be a novel strategy in antitumor therapy (Blattner et al., 2018; Tang et al., 2015; Yang et al., 2018; Zhang et al., 2013).

expression could be negatively regulated via TGF-β/SMAD4 signaling. SMAD4-deficient cancer cells showed higher CCL15 levels than wild type counterparts, and their inoculation into nude mice resulted in more MDSCs inside the primary tumor (Itatani et al., 2013; Yamamoto et al., 2017). Targeting CCL15-CCR1 signaling either with a CCR1 inhibitor, knockdown of CCL15, or knockout of CCR1 could suppress tumor growth and metastasis (Itatani et al., 2013; Kitamura et al., 2010; Takanori Kitamura et al., 2007; Y. Li, J. Wu, et al., 2016). CCL15 can be therefore used as a novel target in anti-tumor treatment. 5. CX3CL1 and CCL26 recruit MDSCs to tumor site in CX3CR1dependent manner CX3C chemokine receptor 1 (CX3CR1), also known as the fractalkine receptor or G-protein coupled receptor 13 (GPR13), is a transmembrane receptor that mediates leukocytes migration and adhesion (Imai et al., 1997). CX3CR1 is highly expressed in M-MDSCs, and at the lower level in PMN-MDSCs (Zhao et al., 2015). There are two ligands for CX3CR1CX3C Ligand 1 (CX3CL1) and chemokine (CC motif) ligand 26-CCL26. CX3CL1, also known as fractalkine (in humans) and neurotactin (in mice), is expressed by Mφs, DCs, microglial cells, endothelial cells, epithelial cells, neurons and osteoblasts. It can attract monocytes, DCs, Mφs, microglial cells, NK cells, T cells, B cells, mast cells, kupffer cells, smooth muscle cells and tumor cells (M. Lee et al., 2018; W. Liu et al., 2016a,b). The correlation between CX3CL1 expression and the cancer prognosis depends on the cancer type: in breast cancer and hepatocellular carcinoma, high CX3CL1 expression was associated with poor prognosis (Matsubara et al., 2007; Tsang et al., 2013), while it correlated with better prognosis in colorectal cancer and gastric adenocarcinoma (Hyakudomi et al., 2008; Ohta et al., 2005). The absence of CX3CL1 expression in pre-treatment tumors was correlated with the response to the PD-L1 blockade (Herbst et al., 2014) and the high CX3CL1 expression was proposed to recruit M-MDSCs into tumor to increased PD-L1-independent immunosuppression (Okuma et al., 2017). Expression of CX3CR1 was shown to be upregulated by two cyclindependent kinase (CDK) inhibitors (p16 and p21). p16Ink4a and p21Waf1/Cip1 genes were highly expressed in MDSCs in allograft mouse models. CX3CL1-positive tumors exhibited p16 and p21-dependent tumor growth. Also flavopiridol (other CDK inhibitor) enhanced the growth of CX3CL1-positive tumor, while treatment with anti-CX3CL1 antibody suppressed tumor growth. The CX3CL1 was suggested to represent a novel molecular target for cancer therapy, especially in combination with CDK inhibitors (Okuma et al., 2017). CCL26, also called Eotaxin-3, Macrophage inflammatory protein 4alpha (MIP-4-alpha), thymic stroma chemokine-1 (TSC-1), and IMAC, is expressed by Mφs, endothelial cells, epithelial cells and smooth muscles cells. It is chemotactic for eosinophils, basophils, monocytes, NK cells and T cells (Coleman et al., 2016; Jeong et al., 2016; Stubbs et al., 2010; Sugaya, 2015). CCL26 was initially described as a chemoattractant of eosinophils that expressed CCR3 receptor (Kitaura et al., 1999). Recently, CCL26 has been demonstrated to be a functional ligand for CX3CR1 (El-Shazly et al., 2013; Nakayama et al., 2010). CCL26 expression by HCC could recruit CX3CR1+ MDSCs to the tumor tissue. Down-regulation of CCL26 using shRNA or blockade of CX3CR1 in MDSCs using neutralizing antibody could profoundly reduce MDSC recruitment and tumor growth (Chiu et al., 2016). Hypoxia is a common feature of solid tumors. CCL26 can be activated by hypoxiainducible factors (HIFs). Inhibition of HIF-mediated CCL26 expression in HCC with digoxin profoundly suppressed MDSCs recruitment and HCC growth (Chiu et al., 2016). Sorafenib, another HIF inhibitor, the only drug for systemic therapy that is able to modestly prolong the survival of HCC patients, has the ability to decrease the number of MDSCs (Cao et al., 2011; Lin and Wu, 2015; Liu et al., 2012; Ziogas and Tsoulfas, 2017). Whether sorafenib decreases MDSCs recruitment via HIF/CCL26 requires further exploration.

4. CCL15-CCR1 signaling recruits MDSCs to the tumor tissue CCL15, also known as leukotactin-1 (Lkn-1), is a member of the CC chemokine family (Hwang et al., 2004; Youn et al., 1997). It is produced by Mφs and neutrophils (Kwon et al., 2008). CCL15 plays its role through the binding to the CC chemokine receptor, CCR1 (Gerard and Rollins, 2001; Hwang et al., 2004; Ko et al., 2002). It is chemotactic for neutrophils, monocytes, lymphocytes, eosinophils and endothelial cells (Hwang et al., 2004; Lee and Kim, 2010; Shimizu and Dobashi, 2012). The level of CCL15 was elevated in serum and tumor tissue of HCC and colorectal cancer patients, and could be a novel biomarker for HCC and colorectal cancer progression and metastasis (Inamoto et al., 2016; Li et al., 2016a,b,c; Li et al., 2013; Li et al., 2016a,b,c; Yamamoto et al., 2017). In addition, CCL15 was an independent predictor of shorter relapse-free survival (RFS) and poor prognosis (Li et al., 2016; Yamamoto et al., 2017). Patients with CCL15 positive metastases showed a shorter RFS than those with CCL15 negative metastases (Yamamoto et al., 2017). Elevated serum and tumor tissue levels of CCL15 resulted in accumulation of CCR1+MDSCs in tumor tissue (Inamoto et al., 2016; Y. Li, J. Wu, et al., 2016; Y. Li et al., 2013; Y. Li, H. P. Yu, et al., 2016). CCL15 203

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

6. CXCL5/CXCL2/CXCL1 recruit MDSCs to tumor tissue via CXCR2

Yang et al., 2008). In a prostate adenocarcinoma model, PMN-MDSCs were the major immune cell types that infiltrated tumor tissue. Upregulation of Yes-associated protein 1 and thus activation of Hippo signaling pathway, increased the transcription of CXCL5 in cancer cells, and attracted CXCR2+ MDSCs to the tumor tissue. Pharmacological inhibition of CXCR2 impeded tumor progression and prolonged survival of prostate cancer patients (G. C. Wang et al., 2016). CXCL2, also called macrophage inflammatory protein 2-alpha (MIP2α), is a chemokine secreted by monocytes, Mφs, Kupffer cells, hepatocytes, and fibroblasts. CXCL2 is a chemotactic factor for neutrophils and hematopoietic stem cells (Dyskova et al., 2017; Mylonas et al., 2017; Noh et al., 2018; C. C. Qin et al., 2017). The elevated expression of CXCL2 coincided with higher number of MDSCs in bladder cancer tissues, and was associated with disease stage and poor prognosis. Bladder cancer cell line could secret CXCL2 that stimulated mitogen-activated protein kinase and nuclear factor kappa B (NF-κB) pathways in MDSCs and chemoattracted MDSCs in CXCR2dependent way (H. Zhang et al., 2017a,b). Ovarian cancer cell line secreted CXCL1/CXCL2 unregulated by Snail through NF-κB pathway and attracted PMN-MDSCs into the tumor in CXCR2-dependent manner. Snail down regulation or CXCR2 antagonist significantly reduced tumor MDSCs infiltration and affected tumor growth (Taki et al., 2018). When accumulation of MDSCs in tumor was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, the efficacy of the antiPD1 treatment in rhabdomyosarcoma or in renal cell carcinoma (Renca) improved (Highfill et al., 2014; Najjar et al., 2017). CXCL1 is also known as keratinocytes-derived chemokine (KC) in mice and as growth-regulated oncogene alpha (GROα) in humans. It is expressed by monocytes, Mφs, neutrophils, epithelial cells, hepatocytes, hepatic stellate cells, astrocytes, keratinocytes and some tumors including colorectal cancer, leukemia, melanoma, and breast cancer. CXCL1 possesses neutrophil and monocyte chemoattractant activity (Hatfield et al., 2010; Ma et al., 2018; W.-P. Shi et al., 2018; Silva et al., 2017; Su et al., 2018; Verbeke et al., 2011; Lei Wang et al., 2018a,b,c; Wu et al., 2018). In murine orthotopic colorectal cancer model, VEGFA, secreted by cancer cells, could stimulate tumor-associated Mφs to produce CXCL1, recruit CXCR2-positive PMN-MDSCs from the blood into premetastatic liver, and promote liver metastasis (D. Wang et al., 2017). The antitumor effect of metformin is mediated by enhancing AMPK phosphorylation and inducing DACH1 expression, leading to NF-kB inhibition and decreased CXCL1 expression, thus inhibition of MDSC migration via CXCR2 (G. Qin et al., 2018). Zhang and colleagues studied the liver immune response of B16 melanoma mice using concanavalin A-induced hepatitis model and found an immune suppression phenotype with the large numbers of MDSCs accumulated in the liver. The levels of CXCL1, CXCL2, CXCL5, and their receptor CXCR2 were elevated in the liver of tumor-bearing mice. When B16 tumor cells were inoculated into CXCR2-/- mice, the recruitment of MDSCs into the liver was significantly impaired, indicated that CXCL1/2/5-CXCR2 signaling was responsible for recruitment of MDSCs into the liver (Hongru Zhang et al., 2017a,b).

CXCR2 is a G-protein-coupled cell surface chemokine receptor. It was cloned in 1991 from a human neutrophil cell line as a binding partner for IL-8 (CXCL8) (Murphy and Tiffany, 1991). Since then, other high-affinity binding partners have been identified, including CXCL1, 2, 3, 5, 6, and 7. CXCR2 has been found on neutrophils, mast cells, monocytes, Mφs, endothelial cells, epithelial cells and multiple tumor cells (Hertzer et al., 2013). CXCR2 expression was upregulated and significantly associated with tumor size, it is an unfavorable predictor in patients with laryngeal squamous cell carcinoma, lung cancer, pancreatic ductal carcinoma, clear-cell renal cell carcinoma and hepatocellular carcinoma(An et al., 2015; Qiao et al., 2018; Yong Yang et al., 2017a,b). CXCR2 has three chemokine ligands associated with MDSCs chemotaxis - C-X-C motif chemokine 5 (CXCL5), C-X-C motif ligand 2 (CXCL2) and C-X-C motif ligand 1 (CXCL1). CXCL5, also known as epithelial-derived neutrophil-activating peptide 78 (ENA-78), is secreted by both immune (neutrophils, eosinophils, monocytes, Mφs, astrocytes, and microglia) and nonimmune (epithelial, endothelial, fibroblast, bladder cancer, prostate cancer, lung cancer, and hepatoma) cells. CXCL5-CXCR2 interaction can attract neutrophils (Begley et al., 2008; Layhadi et al., 2018; O’Sullivan et al., 2018; Persson et al., 2003; Soler-Cardona et al., 2018; C. Wang et al., 2018a; Lin Wang et al., 2018a,b,c; Yang Yang et al., 2017a,b; H. Y. Zhang et al., 2010). CXCL5 is over-expressed in many cancers including intrahepatic cholangiocarcinoma, prostate cancer, gastric cancer, head and neck squamous cell carcinoma, renal cell carcinoma, bladder cancer, and it correlates with tumor progression, migration, prognosis and survival (Begley et al., 2008; Gao et al., 2015; Kawamura et al., 2012; Kowalczuk et al., 2014; Kuo et al., 2011; A. H. Li et al., 2011; Miyazaki et al., 2006; Wong et al., 2007; S. L. Zhou et al., 2014). Yet, CXCL5 was found to inhibit tumor progression in colorectal cancer and renal cell carcinoma (Lopez-Lago et al., 2013; Speetjens et al., 2008). This discrepancy can probably be explained in part by CXCL5 multiple biological functions, including the recruitment of various immune cells into the tumor that either inhibit or promote tumor growth. Here, we focus on CXCL5 role in attracting myeloid-derived suppressor cells to the tumor site. In murine spontaneous melanoma model, CXCL5 was the main chemokine to recruit PMN-MDSCs to the tumor site, and these PMNMDSCs induced epithelial-mesenchymal transition, thus facilitating tumor cell motility, dissemination, and metastasis (Toh et al., 2011). There are various transcription factors and signaling pathways identified that control CXCL5 expression. In xenograft mouse model of gastric cancer, induction of Sphingosine-1-phosphate signaling pathway using specific agonist (SEW-2871) resulted in augmented expression of CXCL5, CXCL12, and CCL2 chemokines, and led to increased numbers of tumor-infiltrating MDSCs. MDSCs migration was partially inhibited with CXCR2 antagonist (SB-265610) that suggested CXCL5-CXCR2 interaction might play a role in MDSCs recruitment (Y. Zhou and Guo, 2018). In 4T1 breast cancer mouse model, Kruppel-like factor 4 (KLF4) could induce the expression of CXCL5 and thus, the production of granulocyte macrophage colony-stimulating factor (GM-CSF) for the maintenance of MDSCs in bone marrow. This effect was inhibited by anti-GM-CSF antibodies, suggesting that CXCL5-mediated GM-CSF upregulation promoted the accumulation of MDSCs in the bone marrow. Meanwhile, CXCL5 was able to recruit MDSCs to the tumor site via CXCR2 and led to the progression of breast cancer. Knockdown of KLF4 retarded tumor growth, inhibited pulmonary metastasis and decreased the number of MDSCs in the bone marrow, the spleen and tumor tissue (Yu et al., 2013). The deficiency of type II TGF-β receptor (Tgfbr2) led to the upregulation of CXCL5 in breast cancer cells, which contributed to accumulation of MDSCs in the tumor site in CXCR2-dependent manner (L.

7. CXCL8 (IL-8) recruited MDSCs to tumor site via CXCR1/CXCR2 CXCL8, chemokine (C-X-C motif) ligand 8, also known as IL-8, can be produced by Mφs, endothelial cells, epithelial cells and tumors, including lymphoma, breast cancer, prostate cancer, lung cancer, and melanoma. It can attract neutrophils, Mφs, DCs, mast cells, endothelial cells, and keratinocytes via its receptors CXCR1 (IL-8Rα) and CXCR2 (IL-8Rβ) (Alfaro et al., 2017; Balkwill, 2004; Ha et al., 2017; Q. Liu et al., 2016a,b; Long et al., 2016). CXCL8 expression is elevated in various cancer types, including breast, colon, ovarian, pancreatic, prostate, and hematological malignancies (AML, CLL, Hodgkin’s lymphoma) (Chi et al., 2014; David et al., 2016; Xie, 2001). The up-regulated CXCL8 reflects poor tumor 204

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

with either knockdown (CCL21low) or overexpression (CCL21high) of CCL21 were implanted into immune competent mice, CCL21high tumors grew much larger than CCL21low tumors. Tumor-produced CCL21 led to increased recruitment of regulatory T cells, TGF-β1, M2 macrophages, and MDSCs to the tumor tissue. This effect was CCR7-dependent, because tumors grew poorly in CCR7-deficient mice or in wild-type mice treated systemically with CCR7-blocking antibodies (Shields et al., 2010). CCL21 role in immune cells recruitment into tumor tissue and its effect on tumor growth require further research.

differentiation, high tumor burden, metastasis, diminished survival and predicts poor prognosis (Benoy et al., 2004; Cacev et al., 2008; Highfill et al., 2014; Kido et al., 2001; Sanmamed et al., 2014; Waugh and Wilson, 2008). The high serum levels of CXCL8 were correlated with the increased frequencies of circulating MDSCs in melanoma (Rudolph et al., 2014), prostate cancer patients (Chi et al., 2014), head and neck cancer patients (Trellakis et al., 2011, 2013), breast, esophageal, colon, and pancreatic cancer patients (Diaz-Montero et al., 2009). Asfaha and colleagues generated transgenic mouse with a physiologically regulated CXCL8 expression (IL-8 Tg). CXCL8 expression contributed to increased colorectal tumorigenesis and gastric carcinogenesis. Tumor-bearing IL-8 Tg mice showed increased mobilization of MDSCs into the tumor and significantly higher numbers of MDSCs in the spleen and the bone marrow (Asfaha et al., 2013). In coimplantation experiments of CT-26 BALB/c mouse colon cancer cells with MDSCs (either from WT or from IL-8 transgenic mice) in NOD-SCID mice, the growth of xenograft tumors was enhanced with MDSCs from IL-8 Tg as compared to MDSCs from WT mice. Both, CT-26 cells and MDSCs expressed CXCL8 receptors - CXCR1 and CXCR2. Co-implantation of IL-8-expressing MDSCs remodeled tumor microenvironment and promoted tumor growth via the increased stromal expansion, higher numbers of cancer-associated fibroblasts, elevated epithelial cell proliferation, and enhanced angiogenesis (Asfaha et al., 2013). Tumorderived CXCL8 could attract MDSCs to the tumor site in CXCR1- and CXCR2-dependent manner (Asfaha et al., 2013; David et al., 2016; Highfill et al., 2014; Katoh et al., 2013). Targeting CXCL8 signaling has been employed in preclinical and clinical settings (Ginestier et al., 2010; Highfill et al., 2014; Schott et al., 2017; Zheng et al., 2015). Reparixin is a pharmacological inhibitor of CXCR1 and CXCR2 (Citro et al., 2012, 2015). In human colon adenocarcinoma HT29 xenograft tumors and colon carcinoma CT26GM-derived subcutaneous tumors, reparixin treatment caused the decrease of PMN-MDSCs numbers in the liver (Alfaro et al., 2016). HuMax-IL8, anti–IL-8 monoclonal antibody, could reduce the number of PMN-MDSCs in the tumor tissue in MDA-MB-231 breast cancer xenografts, even more efficiently when combined with docetaxel (cytotoxic chemotherapeutic agents) (Dominguez et al., 2017). IL-8 levels could determine response to treatment with sunitinib (a receptor tyrosine kinase inhibitor). Sunitinib was demonstrated to effectively target MDSCs, significantly reducing their accumulation in renal cell carcinoma patients, and renal cell carcinoma (Renca), and colon carcinoma (CT26) mouse models, but was ineffective in murine mammary tumor (4T1)-bearing mice. IL-8 likely contributed to sunitinib resistance via recruitment of MDSCs into the tumor and induction of pro-angiogenic pathways (Finke et al., 2011). The plasma levels of CXCL8 were increased in clear cell renal cell carcinoma patients and mouse model that were refractory to sunitinib. Administration of antiIL-8 antibody restored tumor sensitivity to sunitinib, suggesting CXCL8 levels might predict clinical response to sunitinib and serve as a potential target in anti-cancer therapy (D. Huang et al., 2010).

CXCL13, chemokine (C-X-C motif) ligand 13 (CXCL13), also known as B lymphocyte chemoattractant (BLC) or B cell-attracting chemokine 1 (BCA-1), can be produced by DCs, T follicular helper cells, prostate cancer cells, Jurkat cells, cancer-associated myofibroblasts. It attracts mainly B cells, small subsets of CD4+ and CD8+T cells, and skin-derived migratory DCs in CXCR5-dependent manner (Fan et al., 2017; Finch et al., 2013; Garg et al., 2017; Gu-Trantien et al., 2017; J. Li et al., 2018; Muller et al., 2003; Schiffer et al., 2015). CXCL13/CXCR5 axis plays a pivotal role in the progression of many cancers, including neuroblastoma, prostate cancer, breast cancer, HCC, oral squamous cell carcinoma, colorectal cancer, and extranodal NK/Tcell lymphoma (Airoldi et al., 2008; Ammirante et al., 2014; Biswas et al., 2014; El-Haibi et al., 2013; Garg et al., 2017; Kim et al., 2015; Bing Li et al., 2017; Qi et al., 2014; Sambandam et al., 2013; Singh et al., 2009a, 2009b). CXCR5 and CXCL13 tumor levels were associated with poor overall and relapse-free survival of colon cancer patients (Qi et al., 2014). High CXCL13 serum levels were associated with poor progression-free survival in extranodal NK/T-cell lymphoma (Kim et al., 2015). Serum levels of CXCL13 have been proposed as a biomarker of HCC and prostate cancer progression (Bing Li et al., 2017; Singh et al., 2009a, 2009b). CXCR5 and CXCL13 might predict survival outcomes in colon cancer and extranodal NK/T-cell lymphoma patients (Kim et al., 2015; Qi et al., 2014). During work on this manuscript we found only one report about the role of CXCL13/CXCR5 axis in recruitment of MDSCs into tumor site (Ding et al., 2015). In murine MFC gastric cancer CXCL13-CXCR5 interaction played a critical role in the recruitment of CD40+MDSCs into the tumor tissue. CD40 was found to be essential for CXCR5 expression in MDSCs. In CD40 knockout mice, CXCR5 expression was almost nondetectable in MDSCs, less MDSCs were accumulated in the tumor tissue that led to delayed tumor growth and smaller tumor size (Ding et al., 2015). In murine prostate cancer, targeting CXCL13 or its receptor CXCR5 impaired tumor migration (Garg et al., 2017). Before developing CXCL13-CXCR5-specific therapies, more studies are required to address the role of CXCL13/CXCR5 axis in MDSCs recruitment into tumor and to determine the factors that control CXCL13/CXCR5 signaling.

8. CCL21-CCR7 signaling attracts MDSCs to tumor tissue

10. Concluding remarks

CCL21, also known as 6Ckine or secondary lymphoid tissue chemokine (SLC), is a member of the CC chemokine family (Nagira et al., 1997). CCL21 is mainly expressed by endothelial cells, it can also be expressed by fibroblastic reticular cells, astrocytes, microglia and neurons. CCL21 can attract B cells, T cells, DCs, and microglia via CCR7 (Forster et al., 2008; Mburu et al., 2006; Nguyen et al., 2017). CCL21 has both anti-tumor and pro-tumor properties (Forster et al., 2008; Nguyen et al., 2017). CCL21 could exert anti-tumor effect and inhibit lung cancer growth by enhancing the infiltration of CCR7+T cells and reducing the frequency of MDSCs (Kar et al., 2011). Whereas, CCL21 could also induce tumor immunosuppression by MDSCs recruitment. Melanoma cells could secret CCL21. When melanoma cells

Chemokines and their receptors promote migration of leukocytes to specific sites, modulate host immune response and other physiological processes. However, this system is also considered to play a role in the development, progression and metastasis of tumors. Described chemokines are expressed in various cell types, including leukocytes, endothelial cells, epithelial cells, fibroblasts, and cancer cells, and they promote the migration of myeloid-derived suppressor cells to the tumor site that results in suppression of anti-tumor immune response (summarized in Table 1 and Table 2). Some of presented chemokines have multiple effects on MDSCs, can induce the generation of MDSCs in the bone marrow, promote the proliferation of MDSCs, maintain the suppressive function of MDSCs and induce myeloid cells differentiation

9. CXCL13-CXCR5 signaling mediates the migration of MDSCs to tumor tissue

205

Tumor cells

3 L L lung cancer model

206

LLC, spindle cell tumor

HCC

CCL26

Tumor tissue

Gastric cancer

CX3CL1

Hematopoietic CCL5 (BM)

Orthotopic and spontaneous mammary tumors

HCC cell line (Hepa 1–6, MM189, HLE, PLC/PRF/5, MHCC-97 L)

Tumor cells

Colorectal cancer cells

ND

S.c. melanoma cell line B16-F10 model

Tumor cells

C1-TRAMP prostate cancer tumor model

MDSCs

M-MDSCs

PMN-MDSCs, M-MDSCs

PMN-MDSCs, M-MDSCs

PMN-MDSCs, M-MDSCs

MDSCs

PMN-MDSCs

PMN-MDSCs, M-MDSCs

MDSCs

Tumor cells

M-MDSCs, PMN-MDSCs

MDSCs

MDSCs

Tumor tissue

Orthotopic xenograft human colorectal cancer model

(Chiu et al., 2016)

(Inamoto et al., 2016) (Okuma et al., 2017)

(Liu Yang et al., 2018)

(Y. Zhang et al., 2013)

(Tang et al., 2015)

(Hawila et al., 2017)

(Blattner et al., 2018)

(B. Huang et al., 2007) (Y. Zhou and Guo, 2018)

(Chun et al., 2015)

(Hartwig et al., 2017)

(Liang et al., 2017)

(Hale et al., 2015)

(A. L. Chang et al., 2016)

Reference

(continued on next page)

GL261 tumor-derived CCL20 and osteoprotegerin induced CCL2 production by macrophages and microglia, and CCL2 attracted M-MDSCs into tumor Tumor-associated Mφs produced CCL2 and induced recruitment of MDSCs into the tumor Radiation-activated STING pathway induced the expression of CCL2, CCL7, and CCL12 in tumor, which mobilized CCR2 positive M-MDSCs into the tumor and mediated radio-resistance TRAIL/TRAIL-R induced CCL2 expression via CCR2 in a FADDdependent manner, and CCL2 promoted MDSCs accumulation in the tumor CCL2 drove MDSCs accumulation in the colon as dysplasia developed, CCL2 enhanced the suppressive function of PMNMDSCs by increasing ROS production and decreasing T cell receptor ς chain Tumor cell-secreted CCL2 mediated the migration of MDSCs into tumor via CCR2 Activation of S1P/S1P1 signaling pathway induced the expression of CCL2 in tumor cells, resulting in CCR2-dependent accumulation of MDSCs into tumor site Correlated with the progression of melanoma, CCR5+ MDSCs displayed stronger immunosuppressive phenotype and function than CCR5− MDSCs CCR5 ligands induced proliferation of PMN-MDSCs in the bone marrow, CCR5 directed MDSCs mobilization from the bone marrow to the blood, and to the tumor site MDSCs accumulated in the tumor. Treatment with anti-CCR5 antibody reduced the percentage of MDSCs and their suppressive activity in the tumor CCL5 played a pivotal role in the generation of MDSCs in the bone marrow, and played a dual role in promoting 4T1 tumor growth and lung metastasis CCL5 and CCR5 levels were increased in blood and tumor tissue of TB mice. Anti-CCR5 treatment decreased PMN-MDSCs and MMDSCs numbers in the blood and the tumor, enhancing anti-PD1 efficacy CCL15 chemoattracted CCR1+MDSCs to tumor tissue, which was negatively regulated by SMAD4 P16 and p21 upregulated CX3CR1 expression in M-MDSCs. Deletion of p16 and p21 reduced CX3CR1 expression, thereby inhibiting M-MDSCs accumulation in tumors and suppressing the tumor progression CCL26 produced by HCC could recruit CX3CR1+ MDSCs to tumor tissue

CCR2+Ly6C+ M- MDSCs

Ly6C+M-MDSCs, Ly6G+ PMNMDSCs CCR2+Ly6Chi M-MDSCs

Main findings

MDSC subsets

Tumor cells

Ret transgenic melanoma mice

H22 hepatocarcinoma cell line, melanoma B16F1 cell line MFC mouse gastric cancer model

CCL15

CCR5 ligands (CCL3, CCL4, CCL5)

Tumor cells

MC38 colon tumors and Lewis lung carcinoma (LLC)

Epithelial cells and infiltrating lamina propria immune cells

DCs, B, Mφs

Renca (renal tumor)

T-bet−/− Rag2−/− mice (develop colonic dysplasia and adenocarcinoma), Colon-26 colonic adenocarcinoma transplantation model

Macrophages and microglia

GL261 glioma

CCL2

Source of chemokine

Tumor

Chemokine

Table 1 Chemokines promote the migration of MDSCs to the tumor tissue (mouse model).

B.-H. Li, et al.

Molecular Immunology 117 (2020) 201–215

207

ND – not determined.

ND

A-498, 786-O, SN12C renal cancer cell xenogragts

4T1-bearing mice

MDA-MB-231 breast cancer xenografts

MDSCs from human CXCL8 transgenic mice Human tumor cells (MDA-MB231) ND

ND

ND

MDSCs

PMN-MDSCs

MDSCs

CXCR2+CD11b+Ly6Ghi MDSCs

PMN-MDSCs

Tumor- associated macrophages

CT-26 BALB/c mouse colon xenograft cancer model

Rhabdomyosarcoma (RMS)

CXCL8

MDSCs

PMN-MDSCs

MDSCs

PMN-MDSCs

PMN-MDSCs

Liver tissue

Ovarian cancer cells

Ovarian cancer

B16 melanoma mice with ConcanavalinA-induced hepatitis Orthotopic HCT-116 and LS-174 T colorectal cancer

Bladder cancer cells

Bladder cancer

CXCL1

CXCL2

Breast cancer cells Cancer cells

MDSCs

Bone marrow or tumor tissue

4T1 breast cancer

Prostate adenocarcinoma model

MDSCs

Tumor tissue

Spontaneous melanoma model

MDSCs

Tumor cells

MFC mouse gastric cancer model

MDSC subsets

CXCL5

Source of chemokine

Tumor

Chemokine

Table 1 (continued)

Activation of S1P/S1P1 signaling pathway induced the expression of CCL2 in tumor cells, and attracted MDSCs into tumor site in CCR2-dependent way CXCL5 recruited PMN-MDSCs to tumor tissue via CXCR2, PMNMDSCs induced epithelial-mesenchymal transition and facilitated tumor growth KLF4 could induce the production of GM-CSF through CXCL5. GM-CSF could maintain MDSCs in the bone marrow. CXCL5 could also attract MDSCs to tumor tissue via CXCR2 The deficiency of Tgfbr2 led to the upregulation of CXCL5 in breast cancer cells and attracted MDSCs to tumor site via CXCR2 YAP1 increased the transcription of CXCL5, and CXCL5 attracted PMN-MDSCs to tumor tissue in CXCR2-dependent manner Bladder cancer cell line secreted CXCL2, attracted MDSCs via CXCR2 accompanied by the activation of the MAPK and NF-κB pathways in MDSCs Ovarian cancer cell line could secret CXCL1/CXCL2, upregulated by NF-κB/Snail pathway, which attracted PMN-MDSCs to tumor tissue CXCL1/2/5-CXCR2 signaling was responsible for recruitment of MDSCs into the liver Primary cancer cells secreted VEGFA and stimulated tumor associated macrophages to produce CXCL1, and recruited PMNMDSCs to pre-metastatic liver Accumulation of CXCR2+MDSCs in the tumor limited the efficacy of anti-PD1 treatment MDSCs-derived CXCL8 promoted tumor growth and tumor remodeling An anti-CXCL8 monoclonal (HuMax-IL8) could reduce the number of PMN-MDSCs at the tumor site Sunitinib was ineffective in 4T1-bearing mice due to increased intratumoral MDSCs The plasma levels of CXCL8 were elevated in sunitinib-refractory tumor mice, neutralization of CXCL8 activity resensitized renal cell carcinoma to sunitinib treatment

Main findings

(D. Huang et al., 2010)

(Dominguez et al., 2017) (Finke et al., 2011)

(Asfaha et al., 2013)

(Highfill et al., 2014)

(Hongru Zhang et al., 2017a,b) (D. Wang et al., 2017)

(Taki et al., 2018)

(G. C. Wang et al., 2016) (H. Zhang et al., 2017aa, 2017b)

(L. Yang et al., 2008)

(Yu et al., 2013)

(Toh et al., 2011)

(Y. Zhou and Guo, 2018)

Reference

B.-H. Li, et al.

Molecular Immunology 117 (2020) 201–215

208 ND Tumor cells, neutrophils, and probably PMN-MDSCs Tumor stromal cells or infiltrating MDSCs Tumor tissue

Prostate cancer

Head and neck cancer

ND – not determined.

ND

Melanoma

Renal cell carcinoma

Tumor cells

Pediatric sarcomas

CXCL8

Tumor tissue

Bladder cancer

CXCL2

Tumor tissue

HCC

CCL26

CCL15

Tumor tissue

Breast tumor cells

Stage II breast cancer

Colorectal cancer

Tumor tissue

CCR5 ligands (CCL3, CCL4, CCL5)

ND

Epithelial cells and infiltrating lamina propria immune cells Tumor tissue

Colitis-associated colorectal cancer Breast, gastric,and ovarian cancers Melanoma

+

+

+

−

−

low

MDSCs

ND

MDSCs

PMN-MDSCs

CD33 CD11b HLA-DR CD14 MDSCs

+

CD11b CD33 CD14 HLA-DR

+

CD33+CD11b+ HLA-DR− MDSCs, CD33+CD11b− HLA-DR−MDSCs CXCR2+CD11b+Ly6Ghi MDSCs

MDSCs

PMN-MDSCs, M-MDSCs

ND

PMN-MDSCs M-MDSCs

Lin−HLA-DR− MDSCs

MDSCs

Tumor tissue

Lung adenocarcinoma

Serum CCL15 levels in colorectal cancer patients were significantly higher than in controls; tumor CCL15 expression was associated with loss of SMAD4 and the accumulation of MDSCs in the tumor CCL26 was significantly overexpressed in HCC tissue compared with the corresponding non-tumorous liver tissues, and was tightly correlated with hypoxia in human HCCs. MDSCs localized in hypoxic region CXCL2 expression and the number of MDSCs in tumor were increased compared with tumor-adjacent tissues in bladder cancer, which was associated with disease stage and poor prognosis Elevated serum CXCL8 production in pediatric sarcoma patients compared with healthy controls, was associated with diminished survival of patients MDSCs were elevated among all stages, and correlated with the increased level of CXCL8 in the serum of melanoma patients High levels of circulating MDSCs were associated with increased serum levels of CXCL8 and correlated with cancer stage The serum levels of CXCL8 were correlated with the frequencies of tumorinflitrated PMN-MDSCs Sunitinib was ineffective in renal cell carcinoma patients due to increased expression of proangiogenic proteins including CXCL8 Serum and tumor CXCL8 levels were increased in human renal cell carcinoma that were refractory to sunitinib, and may serve as a useful biomarker to predict clinical response of patients to sunitinib treatment

The frequencies of CCR5+PMN-MDSCs and M-MDSCs in peripheral blood and tumor tissue of melanoma patients were increased compared to healthy donors The tumor CCL5 levels correlated with disease progression

Elevated tumor levels of CCL2 correlated with MDSCs markers and reduced overall survival of patients, might serve as an important prognostic factor for survival TRAIL and CCL2 correlated with M2-like myeloid cell accumulation within human tumors Tumor CCL2 levels were significantly higher in areas of adenocarcinoma compared to active colitis or dysplasia Tumor tissue-secreted CCL2 could attract human blood MDSCs via CCR2

CD33+CD14+MDSCs

CD163-positive infiltrating macrophages

Glioblastoma multiforme

CCL2

Main findings

MDSC subsets

Tumor

Chemokine

Source of chemokine

Table 2 Chemokines promote the migration of MDSCs to the tumor tissue (cancer patients).

(D. Huang et al., 2010)

(Trellakis et al., 2011, 2013) (Finke et al., 2011)

(Highfill et al., 2014) (Rudolph et al., 2014) (Chi et al., 2014)

(H. Zhang et al., 2017a,b)

(Chiu et al., 2016)

(B. Huang et al., 2007) (Blattner et al., 2018) (Yaal-Hahoshen et al., 2006) (Inamoto et al., 2016)

(Hartwig et al., 2017) (Chun et al., 2015)

(A. L. Chang et al., 2016)

Reference

B.-H. Li, et al.

Molecular Immunology 117 (2020) 201–215

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

Fig. 1. The schematic diagram of the chemokines and their receptors involved in the accumulation of MDSCs in tumor. Tumor-derived chemokines, including CCL2/ 12, CCL3/4/5, CCL15, CX3CL1/CCL26, CXCL5/2, CXCL8, CCL21, CXCL13 attract chemokine receptor-positive MDSCs into tumor tissue via CCR2, CCR5, CCR1, CX3CR1, CXCR2, CXCR1/2, CCR7, CXCR5, respectively. CCL2 and CXCL1 secreted by macrophages or microglia in tumor tissue recruit CCR2+ MDSCs and CXCR2+ MDSCs into tumor. CCL15 and CXCL5 are negatively regulated by TGFβ signaling pathway. P16 and p21 could modulate the expression of CX3CL1. HIF could activate CCL26. Hippo pathway could regulate the level of CXCL5. In the bone marrow, CCL3/4/5 and CXCL5 induce the generation, promote the proliferation, and maintain the suppressive function of MDSCs. KLF4 could regulate the expression of CXCL5 in bone marrow.

remains unclear whether CCL19, which is, next to CCL21, another ligand for CCR7, may attract MDSCs to tumor tissue. The expression of chemokines described in this review can be regulated by various signaling pathways (summarized in Table 3). However, there may be other mechanisms regulating the expression of chemokines and their receptors crucial for MDSCs recruitment. It is necessary to clarify the role of CCL21/CCR7 and CXCL13/CXCR5 axes in MDSCs recruitment to tumor tissue, to identify novel chemokine-receptor pairs that via MDSCs recruitment contribute to tumor development and metastasis, and to study underlying signaling pathways. The chemokines that induce recruitment of MDSCs to the tumor tissue described here are often produced by tumor cells, immune cells and epithelial cells. MDSCs were also reported to express chemokines. Zhao and colleagues isolated splenic M-MDSCs and PMN-MDSCs from the orthotopic hepatocellular carcinoma model. They analyzed mRNA levels of 84 chemokines and cytokines, chemokine receptors, and related signaling molecules involved in chemotaxis, including CCL2/3/4/ 5, CXCL1/2/5 and CX3CL1. The authors found that PMN-MDSCs expressed high levels of CCL3/4 and CXCL1, medium levels of CCL2/5 and CXCL1, and low levels of CXCL5 and CX3CL1. M-MDSCs had high expression of CCL2/3/5 and CXCL2, intermediate expression of CXCL1, and low expression of CXCL5 and CX3CL1 (Zhao et al., 2015). CCL3, CCL4 and CCL5 released by tumor-infiltrating M-MDSCs caused CCR5dependent Treg recruitment and favored tumor growth in RMA-S lymphoma or B16 melanoma mouse model (Schlecker et al., 2012). The chemokines produced by tumor-infiltrating MDSCs probably contribute to MDSCs recruitment into the tumor. More studies are required to

into MDSCs (CCL3/4/5, CXCL5, Fig. 1). The frequencies and subsets of MDSCs found in various cancers and tumor models may vary depending on the tumor type, tissue of tumor origin, and chemokine-receptor pair involved in MDSCs recruitment. In the majority of cancers, including breast, lung, pancreatic, colon, renal, head and neck, PMN-MDSCs are the main subset of MDSCs in murine peripheral lymphoid organs and the peripheral blood of cancer patients. M-MDSCs are more frequent in the tumor tissue than in the lymph nodes, spleen or blood (Kumar et al., 2016). However, different ratios of PMN-MDSCs/M-MDSCs are present in different cancer types. For example, higher frequencies of M-MDSCs than PMN-MDSCs were found in the peripheral blood of patients with melanoma and prostate cancer. Such changes could be due to the factors present in the tumor: cytokines, chemokines, growth factors and others, produced by tumor or host cells, which can induce MDSCs migration, survival and affect their distribution and function in different cancers (V. Bronte et al., 2001; Kumar et al., 2016; Solito et al., 2014; J. I. Youn et al., 2008). The tumor is characterized by hypoxia and the inflammatory microenvironment that mediates upregulation of genes involved in more suppressive non-specific functions of MDSCs. Last, but not least, lower levels of PMN-MDSCs found in the tumor might be due to PMN-MDCs loss during isolation (Kumar et al., 2016). There might be other, not-yet identified/well studied chemokinereceptor pairs and underlying signaling pathways involved in MDSCs recruitment to tumor tissue. CCR4 and CCR11 expressed on MDSCs are, next to CCR2, the receptors for CCL2 (Sarvaiya et al., 2013; Zhao et al., 2015), however it needs to be assessed whether CCL2-CCR4/CCR11 axes might recruit MDSCs into tumor microenvironment. Similarly, it

209

Mediates cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression Mediates cell proliferation.

TGF- β/SMAD4

210

Epithelial mesenchymal transition, migration, invasion Regulation of vascular permeability, angiogenesis, vasculogenesis and endothelial cell growth, migration, and inhibition of apoptosis.

Snail/NFkappaB

Vascular endothelial growth factor (VEGFA)

Regulation of cell proliferation and apoptosis.

Hippo

Kruppel-like factor 4 (KLF4)

HIFs (hypoxia inducible factors) Sphingosine-1-phosphate

p16, p21

Inhibitors of the activity of cyclin-dependent kinases in response to a variety of stimuli Transcriptional activators that function as master regulators of oxygen homeostasis Important in the regulation of maturation, structure, migration and trafficking Transcriptional activator or repressor (depending on the promoter context)

Induces cancer cell apoptosis Essential component in DNA sensing and type I IFN production pathway

TRAIL/TRAIL-R STING (stimulator of interferon genes)

type II TGF- β

Function

Signaling pathway

Murine orthotopic colorectal cancer model

Ovarian cancer cell line

Prostate adenocarcinoma model

Xenograft mouse model of gastric cancer 4T1 breast cancer mouse model

HCC

LLC or spindle cell tumor model

Breast cancer cells

TRAIL-resistant lung cancer model Irradiated MC38 colon tumors and Lewis lung carcinoma (LLC) tumor model Colorectal cancer

Tumor

Table 3 Signaling pathways that modulate the expression of chemokines and/or their receptors.

Increased transcription of CXCL5 Upregulated CXCL1/CXCL2 secretion Stimulated tumor-associated Mφs produced CXCL1

Augmented expression of CXCL5, CXCL12 and CCL2 Induced expression of CXCL5

SMAD4-deficient cancer cells showed increased CCL15 levels Upregulation of CXCL5 in breast cancer cells P16 and p21 upregulated the expression of CX3CR1 HIFs activated CCL26

Increased CCL2 expression Induced expression of CCL2, CCL7, CCL12 in tumor

Effect on chemokine/ chemokine receptor

Recruitment of CXCR2-positive PMN-MDSCs from the blood into pre-metastatic liver, leading to liver metastasis

Accumulation of PMN-MDSCs in the tumor

Maintanance of MDSCs in the bone marrow, the spleen and the tumor tissue; the CXCR2-dependent recruitment of MDSCs to the tumor site that promoted the progression of breast cancer Recruitment of CXCR2+ MDSCs to tumor tissue

CX3CL1-positive tumors exhibited p16 and p21-dependent tumor growth. Inhibition of HIF-mediated CCL26 expression in HCC suppressed MDSCs recruitment and HCC growth Increased numbers of tumor-infiltrating MDSCs

Recruitment of MDSCs to tumor site

Inoculation of SMAD4-deficient cancer cells into nude mice resulted in more MDSCs inside the primary tumor

CCR2-dependent accumulation of MDSCs in the tumor Mobilization of CCR2-positive M-MDSCs to the tumor that resulted in radio-resistance

Effect on tumor

(D. Wang et al., 2017)

(G. C. Wang et al., 2016) (Taki et al., 2018)

(Y. Zhou and Guo, 2018) (Yu et al., 2013)

(Chiu et al., 2016)

(Okuma et al., 2017)

(Itatani et al., 2013; Yamamoto et al., 2017) (L. Yang et al., 2008)

(Hartwig et al., 2017) (Liang et al., 2017)

References

B.-H. Li, et al.

Molecular Immunology 117 (2020) 201–215

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

Table 4 Inhibition of MDSCs (solo and combination treatments). Target

Agent

Effect on tumor

References

CCL2-CCR2

CCL2 neutralizing antibody (solo or in combination with chemotherapeutic drug docetaxel) CCL2 neutralizing antibody and anti-CCR2 antibody Anti-CCR2 antibody

Significant therapeutic effects observed in preclinical model of cancer growth in bone

(Kirk et al., 2013)

Hindered MDSCs migration into tumor and MDSCs-mediated tumor growth Reversed the radio-resistance and improved anti-tumor efficacy in irradiated tumor-bearing mice Reduced the number and the immunosuppressive potential of tumor-infiltrating MDSCs, inhibited metastasis, improved the survival of tumor-bearing mice, and enhanced the efficacy of antiPD1 cancer treatment Blocked MDSCs accumulation in tumor and metastatic colonization. Significantly prolonged the survival of tumor-bearing mice Suppressed tumor growth Profoundly reduced MDSCs recruitment and tumor growth Inhibition of HIF-mediated CCL26 expression in HCC with digoxin profoundly suppressed MDSCs recruitment and HCC growth Decreased the number of MDSCs in the bone marrow and the spleen MDSCs migration was partially inhibited

(B. Huang et al., 2007)

CCL3/4/5-CCR5

mCCR5-Ig fusion protein, anti-CCR5 antibody, or CCL5-neutralizing mAb

CCL15-CCR1

CCR1 antagonist BL5923

CX3CL1/CCL26CX3CR1

anti-CX3CL1 antibody Anti-CX3CR1 neutralizing antibody Digoxin (HIF inhibitor CCL26 donwregulation)

CXCR1/2

Sorafenib, another HIF inhibitor Unknown effect on chemokines or their receptors CXCR2 antagonist (SB-265610) Pharmacological inhibition of CXCR2 anti-CXCR2 monoclonal antibody

Reparixin, a pharmacological inhibitor of CXCR1 and CXCR2 IL-8-CXCR1/2

HuMax-IL8, anti–IL-8 monoclonal antibody (solo or in combination with docetaxel - cytotoxic chemotherapeutic agent) anti-IL-8 antibody

Impeded tumor progression and prolonged survival of prostate patients The accumulation of MDSCs in tumor decreased, the efficacy of the anti-PD1 treatment in rhabdomyosarcoma and in Renca tumor improved In HT29 xenograft tumors and CT26-GM-derived subcutaneous tumors, reparixin treatment caused the decrease of PMN-MDSCs numbers in the liver Could reduce the number of PMN-MDSCs in the tumor tissue in MDA-MB-231 breast cancer xenografts Restored tumor sensitivity to sunitinib

(Liang et al., 2017) (Blattner et al., 2018; Tang et al., 2015; Liu Yang et al., 2018; Y. Zhang et al., 2013) (T. Kitamura et al., 2010)

(Okuma et al., 2017) (Chiu et al., 2016) (Chiu et al., 2016) (Cao et al., 2011) (Taki et al., 2018; Y. Zhou and Guo, 2018) (G. C. Wang et al., 2016) (Highfill et al., 2014; Najjar et al., 2017) (Alfaro et al., 2016; Citro et al., 2012, 2015) (Dominguez et al., 2017)

(D. Huang et al., 2010)

BHL wrote the manuscript, prepared the figure and tables 1 and 2, and reviewed tables 3 and 4. MAG wrote parts of the manuscript, prepared Table 3 and 4, and reviewed the manuscript, the figure and tables 1 and 2. All authors read and approved the final version of the manuscript.

assess the secretion of chemokines by MDSCs in various cancer types. Blocking MDSCs recruitment into tumor can be used as an effective anti-tumor therapeutic strategy (Table 4) (Martin et al., 2012). The efficacy might be improved when used in combination with various known anti-cancer therapies, including anti-PD1 treatment. Targeting chemokine receptors might be other treatment option (Table 4). However, since some chemokines described in this review, including CCL2, CCL12, CCL5, and CCL15, can also recruit effector cells (including NK cells, T lymphocytes) pivotal for tumor clearance, targeting these chemokines might decrease the number of MDSCs as well as the effector cells. It is therefore crucial to weight pro and cons of targeting these chemokines in anti-cancer therapy for the best outcome for the patients. In tumor-bearing host, MDSCs accumulate in lymphoid tissue, peripheral blood, and tumor. Most published studies focus on the recruitment of MDSCs to tumor tissue, fewer on the mechanism of MDSCs accumulation in the lymphoid organs, including the spleen - the largest lymphoid organ in the body. Spleen might be a reservoir of MDSCs. Splenectomy at the tumor progressive stage could significantly lower the number of MDSCs both in peripheral blood and tumor tissue (L. Levy et al., 2015; B. Li et al., 2016a,b). In addition, the spleen might be the primary site of MDSCs proliferation, that would explain MDSCs accumulation in the spleen of tumor-bearing mice (Younos et al., 2012). MDSCs subsets, their suppressive activity and their differentiation vary between lymphoid and tumor tissue (Kumar et al., 2016; Maenhout et al., 2014). So, the mechanisms of the accumulation of MDSCs in the spleen may be distinct from the ones described for tumor (Li et al., 2019). The mechanisms of MDSCs accumulation in the spleen require further exploration.

Declaration of Competing Interest The authors declare no conflicts of interests. Acknowledgements This work was supported by the National Natural Science Foundation of China (81001309, 81700691, 81870536, and 91842307), the Key Research and Development Program of Shaanxi Province of China (2017ZDCXL-SF-02-05). References Airoldi, I., Cocco, C., Morandi, F., Prigione, I., Pistoia, V., 2008. CXCR5 may be involved in the attraction of human metastatic neuroblastoma cells to the bone marrow. Cancer Immunol. Immunother. 57 (4), 541–548. Alfaro, C., Sanmamed, M.F., Rodriguez-Ruiz, M.E., Teijeira, A., Onate, C., Gonzalez, A., et al., 2017. Interleukin-8 in cancer pathogenesis, treatment and follow-up. Cancer Treat. Rev. 60, 24–31. Alfaro, C., Teijeira, A., Onate, C., Perez, G., Sanmamed, M.F., Andueza, M.P., et al., 2016. Tumor-produced Interleukin-8 attracts human myeloid-derived suppressor cells and elicits extrusion of neutrophil extracellular traps (NETs). Clin. Cancer Res. 22 (15), 3924–3936. Ammirante, M., Shalapour, S., Kang, Y., Jamieson, C.A.M., Karin, M., 2014. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc. Natl. Acad. Sci. U. S. A. 111 (41), 14776–14781. An, H., Xu, L., Chang, Y., Zhu, Y., Yang, Y., Chen, L., et al., 2015. CXC chemokine receptor 2 is associated with postoperative recurrence and survival of patients with non-metastatic clear-cell renal cell carcinoma. Eur. J. Cancer 51 (14), 1953–1961 (Oxford, England : 1990).

Authorship BHL, MAG, and ZHL developed the manuscript concept and outline. 211

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

conceiving new prognostic and therapeutic targets. Biochimica Et Biophysica Acta Rev. Cancer 1865 (1), 35–48. DeLeon-Pennell, K.Y., Iyer, R.P., Ero, O.K., Cates, C.A., Flynn, E.R., Cannon, P.L., et al., 2017. Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing. JCI Insight 2 (18). 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 doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol. Immunother. 58 (1), 49–59. Ding, Y.X., Shen, J., Zhang, G.B., Chen, X.J., Wu, J.M., Chen, W.C., 2015. CD40 controls CXCR5-induced recruitment of myeloid-derived suppressor cells to gastric cancer. Oncotarget 6 (36), 38901–38911. Dominguez, C., McCampbell, K.K., David, J.M., Palena, C., 2017. Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triplenegative breast cancer. JCI Insight 2 (21). Dyskova, T., Gallo, J., Kriegova, E., 2017. The role of the chemokine system in tissue response to prosthetic by-products leading to Periprosthetic Osteolysis and aseptic loosening. Front. Immunol. 8 doi: Artn 102610.3389/Fimmu.2017.01026. Eisenblaetter, M., Flores-Borja, F., Lee, J.J., Wefers, C., Smith, H., Hueting, R., et al., 2017. Visualization of tumor-immune interaction - target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment. Theranostics 7 (9), 2392–2401. El-Haibi, C.P., Sharma, P., Singh, R., Gupta, P., Taub, D.D., Singh, S., Lillard Jr, J.W., 2013. Differential G protein subunit expression by prostate cancer cells and their interaction with CXCR5. Mol. Cancer 12, 64. El-Shazly, A.E., Doloriert, H.C., Bisig, B., Lefebvre, P.P., Delvenne, P., Jacobs, N., 2013. Novel cooperation between CX3CL1 and CCL26 inducing NK cell chemotaxis via CX3CR1: a possible mechanism for NK cell infiltration of the allergic nasal tissue. Clin. Exp. Allergy 43 (3), 322–331. https://doi.org/10.1111/cea.12022. Fan, L., Zhu, Q., Liu, L., Zhu, C., Huang, H., Lu, S., Liu, P., 2017. CXCL13 is androgenresponsive and involved in androgen induced prostate cancer cell migration and invasion. Oncotarget 8 (32), 53244–53261. Filipazzi, P., Huber, V., Rivoltini, L., 2012. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol. Immunother. 61 (2), 255–263. Finch, D.K., Ettinger, R., Karnell, J.L., Herbst, R., Sleeman, M.A., 2013. Effects of CXCL13 inhibition on lymphoid follicles in models of autoimmune disease. Eur. J. Clin. Invest. 43 (5), 501–509. Finke, J., Ko, J., Rini, B., Rayman, P., Ireland, J., Cohen, P., 2011. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int. Immunopharmacol. 11 (7), 856–861. Forster, R., Davalos-Misslitz, A.C., Rot, A., 2008. CCR7 and its ligands: balancing immunity and tolerance. Nat. Rev. Immunol. 8 (5), 362–371. Gabrilovich, D.I., 2017. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5 (1), 3–8. Gabrilovich, D.I., Nagaraj, S., 2009. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9 (3), 162–174. https://doi.org/10.1038/ nri2506. Gabrilovich, D.I., Ostrand-Rosenberg, S., Bronte, V., 2012. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12 (4), 253–268. Gao, Y., Guan, Z.F., Chen, J.Q., Xie, H.J., Yang, Z., Fan, J.H., et al., 2015. CXCL5/CXCR2 axis promotes bladder cancer cell migration and invasion by activating PI3K/AKTinduced upregulation of MMP2/MMP9. Int. J. Oncol. 47 (2), 690–700. https://doi. org/10.3892/ijo.2015.3041. Garg, R., Blando, J.M., Perez, C.J., Abba, M.C., Benavides, F., Kazanietz, M.G., 2017. Protein kinase C epsilon cooperates with PTEN loss for prostate tumorigenesis through the CXCL13-CXCR5 pathway. Cell Rep. 19 (2), 375–388. Gerard, C., Rollins, B.J., 2001. Chemokines and disease. Nat. Immunol. 2 (2), 108–115. Ginestier, C., Liu, S., Diebel, M.E., Korkaya, H., Luo, M., Brown, M., et al., 2010. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J. Clin. Invest. 120 (2), 485–497. Gu-Trantien, C., Migliori, E., Buisseret, L., de Wind, A., Brohee, S., Garaud, S., et al., 2017. CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer. JCI Insight 2 (11). Guan, X., Liu, Z., Zhang, J., Jin, X., 2018. Myeloid-derived suppressor cell accumulation in renal cell carcinoma is correlated with CCL2, IL-17 and IL-18 expression in blood and tumors. Adv. Clin. Exp. Med. 27 (7), 947–953. https://doi.org/10.17219/acem/ 70065. Ha, H., Debnath, B., Neamati, N., 2017. Role of the CXCL8-CXCR1/2 Axis in Cancer and inflammatory diseases. Theranostics 7 (6), 1543–1588. Hale, M., Itani, F., Buchta, C.M., Wald, G., Bing, M., Norian, L.A., 2015. Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2. PLoS One 10 (3), e0118784. https://doi.org/10.1371/journal.pone. 0118784. Hartwig, T., Montinaro, A., von Karstedt, S., Sevko, A., Surinova, S., Chakravarthy, A., et al., 2017. The TRAIL-Induced Cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Mol. Cell 65 (4), 730–742 e735. Hatfield, K.J., Reikvam, H., Bruserud, O., 2010. The crosstalk between the matrix metalloprotease system and the chemokine network in acute myeloid leukemia. Curr. Med. Chem. 17 (36), 4448–4461. Hawila, E., Razon, H., Wildbaum, G., Blattner, C., Sapir, Y., Shaked, Y., et al., 2017. CCR5 directs the mobilization of CD11b + Gr1 + Ly6C low polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development. Cell Rep. 21 (8), 2212–2222. https://doi.org/10.1016/j.celrep.2017.10.104. Herbst, R.S., Soria, J.-C., Kowanetz, M., Fine, G.D., Hamid, O., Gordon, M.S., et al., 2014. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer

Appay, V., Rowland-Jones, S.L., 2001. RANTES: a versatile and controversial chemokine. Trends Immunol. 22 (2), 83–87. Arenberg, D.A., Keane, M.P., DiGiovine, B., Kunkel, S.L., Strom, S.R.B., Burdick, M.D., et al., 2000. Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines. Cancer Immunol. Immunother. 49 (2), 63–70. Asfaha, S., Dubeykovskiy, A.N., Tomita, H., Yang, X., Stokes, S., Shibata, W., 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 (1), 155–166. Baba, T., Mukaida, N., 2014. Role of macrophage inflammatory protein (MIP)-1alpha/ CCL3 in leukemogenesis. Mol. Cell. Oncol. 1 (1), e29899. Balkwill, F., 2004. Cancer and the chemokine network. Nat. Rev. Cancer 4 (7), 540–550. Begley, L.A., Kasina, S., Mehra, R., Adsule, S., Admon, A.J., Lonigro, R.J., et al., 2008. CXCL5 promotes prostate cancer progression. Neoplasia 10 (3), 244–254. https://doi. org/10.1593/neo.07976. Behfar, S., Hassanshahi, G., Nazari, A., Khorramdelazad, H., 2017. A brief look at the role of monocyte chemoattractant protein-1 (CCL2) in the pathophysiology of psoriasis. Cytokine. Benoy, I.H., Salgado, R., Van Dam, P., Geboers, K., Van Marck, E., Scharpe, S., et al., 2004. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin. Cancer Res. 10 (21), 7157–7162. Biswas, S., Sengupta, S., Roy Chowdhury, S., Jana, S., Mandal, G., Mandal, P.K., et al., 2014. CXCL13-CXCR5 co-expression regulates epithelial to mesenchymal transition of breast cancer cells during lymph node metastasis. Breast Cancer Res. Treat. 143 (2), 265–276. Blattner, C., Fleming, V., Weber, R., Himmelhan, B., Altevogt, P., Gebhardt, C., et al., 2018. CCR5+ myeloid-derived suppressor cells are enriched and activated in melanoma lesions. Cancer Res. 78 (1), 157–167. Bottazzi, B., Colotta, F., Sica, A., Nobili, N., Mantovani, A., 1990. A chemoattractant expressed in human sarcoma-cells (Tumor-Derived chemotactic factor, tdcf) is identical to monocyte chemoattractant Protein-1 monocyte chemotactic and activating factor (Mcp-1/Mcaf). Int. J. Cancer 45 (4), 795–797. Bronte, V., Brandau, S., Chen, S.-H., Colombo, M.P., Frey, A.B., Greten, T.F., et al., 2016. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150. Bronte, V., Pittet, M.J., 2013. The spleen in local and systemic regulation of immunity. Immunity 39 (5), 806–818. https://doi.org/10.1016/j.immuni.2013.10.010. Bronte, V., Serafini, P., Apolloni, E., Zanovello, P., 2001. Tumor-induced immune dysfunctions caused by myeloid suppressor cells. J. Immunother. 24 (6), 431–446. Cacev, T., Radosevic, S., Krizanac, S., Kapitanovic, S., 2008. Influence of interleukin-8 and interleukin-10 on sporadic colon cancer development and progression. Carcinogenesis 29 (8), 1572–1580. Cao, M.D., Xu, Y.L., Youn, J.I., Cabrera, R., Zhang, X.K., Gabrilovich, D., et al., 2011. Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab. Investig. 91 (4), 598–608. Chang, A.L., Miska, J., Wainwright, D.A., Dey, M., Rivetta, C.V., Yu, D., et al., 2016. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory t cells and myeloid-derived suppressor cells. Cancer Res. 76 (19), 5671–5682. Chang, T.T., Chen, J.W., 2016. Emerging role of chemokine CC motif ligand 4 related mechanisms in diabetes mellitus and cardiovascular disease: friends or foes? Cardiovasc. Diabetol. 15 doi: Artn 11710.1186/S12933-016-0439-9. Chavey, C., Bibeau, F., Gourgou-Bourgade, S., Burlinchon, S., Boissiere, F., Laune, D., et al., 2007. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res. 9 (1), R15. Chi, N., Tan, Z., Ma, K., Bao, L., Yun, Z., 2014. Increased circulating myeloid-derived suppressor cells correlate with cancer stages, interleukin-8 and -6 in prostate cancer. Int. J. Clin. Exp. Med. 7 (10), 3181–3192. Chiu, D.K.C., Xu, I.M.J., Lai, R.K.H., Tse, A.P.W., Wei, L.L., Koh, H.Y., et al., 2016. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. Hepatology 64 (3), 797–813. Choi, S.J., Cruz, J.C., Craig, F., Chung, H., Devlin, R.D., Roodman, G.D., Alsina, M., 2000. Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 96 (2), 671–675. Chow, M.T., Luster, A.D., 2014. Chemokines in cancer. Cancer Immunol. Res. 2 (12), 1125–1131. https://doi.org/10.1158/2326-6066.CIR-14-0160. Chun, E., Lavoie, S., Michaud, M., Gallini, C.A., Kim, J., Soucy, G., et al., 2015. CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep. 12 (2), 244–257. Citro, A., Cantarelli, E., Maffi, P., Nano, R., Melzi, R., Mercalli, A., et al., 2012. CXCR1/2 inhibition enhances pancreatic islet survival after transplantation. J. Clin. Invest. 122 (10), 3647–3651. Citro, A., Valle, A., Cantarelli, E., Mercalli, A., Pellegrini, S., Liberati, D., et al., 2015. CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice. Diabetes 64 (4), 1329–1340. Coleman, S.L., Kruger, M.C., Sawyer, G.M., Hurst, R.D., 2016. Procyanidin A2 modulates IL-4-Induced CCL26 production in human alveolar epithelial cells. Int. J. Mol. Sci. 17 (11). https://doi.org/10.3390/ijms17111888. Conti, I., Rollins, B.J., 2004. CCL2 (monocyte chemoattractant protein-1) and cancer. Semin. Cancer Biol. 14 (3), 149–154. Cui, T.X., Kryczek, I., Zhao, L.L., Zhao, E.D., Kuick, R., Roh, M.H., et al., 2013. Myeloidderived suppressor cells enhance stemness of Cancer cells by inducing MicroRNA101 and suppressing the corepressor CtBP2. Immunity 39 (3), 611–U222. David, J.M., Dominguez, C., Hamilton, D.H., Palena, C., 2016. The IL-8/IL-8R Axis: a double agent in tumor immune resistance. Vaccines 4 (3). De Sanctis, F., Solito, S., Ugel, S., Molon, B., Bronte, V., Marto, I., 2016. MDSCs in cancer:

212

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

1/CCL15 enhances matrix metalloproteinase-9 release from human macrophages and macrophage-derived foam cells. Nutr. Res. Pract. 2 (2), 134–137. Layhadi, J.A., Turner, J., Crossman, D., Fountain, S.J., 2018. ATP evokes Ca2+ responses and CXCL5 secretion via P2X4 receptor activation in human monocyte-derived macrophages. J. Immunol. 200 (3), 1159–1168 (Baltimore, Md : 1950). Lee, J.-S., Kim, I.S., 2010. Leukotactin-1/CCL15 induces cell migration and differentiation of human eosinophilic leukemia EoL-1 cells through PKCdelta activation. Mol. Biol. Rep. 37 (5), 2149–2156. Lee, M., Lee, Y., Song, J., Lee, J., Chang, S.-Y., 2018. Tissue-specific role of CX3CR1 expressing immune cells and their relationships with human disease. Immune Netw. 18 (1), e5. Lehmann, M.H., Torres-Dominguez, L.E., Price, P.J.R., Brandmuller, C., Kirschning, C.J., Sutter, G., 2016. CCL2 expression is mediated by type I IFN receptor and recruits NK and T cells to the lung during MVA infection. J. Leukoc. Biol. 99 (6), 1057–1064. Lesokhin, A.M., Hohl, T.M., Kitano, S., Cortez, C., Hirschhorn-Cymerman, D., Avogadri, F., et al., 2012. Monocytic CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Res. 72 (4), 876–886. Levy, J.A., 2009. The unexpected pleiotropic activities of RANTES. J. Immunol. 182 (7), 3945–3946. Levy, L., Mishalian, I., Bayuch, R., Zolotarov, L., Michaeli, J., Fridlender, Z.G., 2015. Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response. Oncoimmunology 4 (4), e998469. https://doi. org/10.1080/2162402X.2014.998469. Li, A.H., King, J., Moro, A., Sugi, M.D., Dawson, D.W., Kaplan, J., et al., 2011. Overexpression of CXCL5 is associated with poor survival in patients with pancreatic Cancer. Am. J. Pathol. 178 (3), 1340–1349. https://doi.org/10.1016/j.ajpath.2010. 11.058. Li, B., Su, H., Cao, J., Zhang, L., 2017. CXCL13 rather than IL-31 is a potential indicator in patients with hepatocellular carcinoma. Cytokine 89, 91–97. Li, B., Zhang, S., Huang, N., Chen, H., Wang, P., Li, J., et al., 2016a. Dynamics of the spleen and its significance in a murine H22 orthotopic hepatoma model. Exp. Biol. Med. (Maywood) 241 (8), 863–872. https://doi.org/10.1177/1535370216638772. Li, B., Zhang, S., Huang, N., Chen, H., Wang, P., Yang, J., Li, Z., 2019. CCL9/CCR1 induces myeloidderived suppressor cell recruitment to the spleen in a murine H22 orthotopic hepatoma model. Oncol. Rep. 41 (1), 608–618. https://doi.org/10.3892/ or.2018.6809. Li, J., Qiu, D., Chen, Z., Du, W., Liu, J., Mo, X., 2018. miR-548k regulates CXCL13 expression in myasthenia gravis patients with thymic hyperplasia and in Jurkat cells. J. Neuroimmunol. 320, 125–132. Li, Y., Wu, J., Zhang, P., 2016b. CCL15/CCR1 axis is involved in hepatocellular carcinoma cells migration and invasion. Tumour Biol. 37 (4), 4501–4507. Li, Y., Wu, J., Zhang, W., Zhang, N., Guo, H., 2013. Identification of serum CCL15 in hepatocellular carcinoma. Br. J. Cancer 108 (1), 99–106. Li, Y., Yu, H.P., Zhang, P., 2016c. CCL15 overexpression predicts poor prognosis for hepatocellular carcinoma. Hepatol. Int. 10 (3), 488–492. Liang, H., Deng, L., Hou, Y., Meng, X., Huang, X., Rao, E., et al., 2017. Host STINGdependent MDSC mobilization drives extrinsic radiation resistance. Nat. Commun. 8 (1), 1736. Lim, S.Y., Yuzhalin, A.E., Gordon-Weeks, A.N., Muschel, R.J., 2016. Targeting the CCL2CCR2 signaling axis in cancer metastasis. Oncotarget 7 (19), 28697–28710. Lin, D., Wu, J., 2015. Hypoxia inducible factor in hepatocellular carcinoma: a therapeutic target. World J. Gastroenterol. 21 (42), 12171–12178. https://doi.org/10.3748/wjg. v21.i42.12171. Liu, L.P., Ho, R.L.K., Chen, G.G., Lai, P.B.S., 2012. Sorafenib inhibits hypoxia-inducible Factor-1 alpha synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin. Cancer Res. 18 (20), 5662–5671. Liu, Q., Li, A., Tian, Y., Wu, J.D., Liu, Y., Li, T., et al., 2016a. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev. 31, 61–71. Liu, W., Jiang, L., Bian, C., Liang, Y., Xing, R., Yishakea, M., Dong, J., 2016b. Role of CX3CL1 in diseases. Archivum immunologiae et therapiae experimentalis 64 (5), 371–383. Long, X., Ye, Y., Zhang, L., Liu, P., Yu, W., Wei, F., et al., 2016. IL-8, a novel messenger to cross-link inflammation and tumor EMT via autocrine and paracrine pathways (Review). Int. J. Oncol. 48 (1), 5–12. Lopez-Lago, M.A., Posner, S., Thodima, V.J., Molina, A.M., Motzer, R.J., Chaganti, R.S.K., 2013. Neutrophil chemokines secreted by tumor cells mount a lung antimetastatic response during renal cell carcinoma progression. Oncogene 32 (14), 1752–1760. Ma, K., Yang, L., Shen, R., Kong, B., Chen, W., Liang, J., et al., 2018. Th17 cells regulate the production of CXCL1 in breast cancer. Int. Immunopharmacol. 56, 320–329. Maenhout, S.K., Van Lint, S., Emeagi, P.U., Thielemans, K., Aerts, J.L., 2014. Enhanced suppressive capacity of tumor-infiltrating myeloid-derived suppressor cells compared with their peripheral counterparts. Int. J. Cancer 134 (5), 1077–1090. https://doi. org/10.1002/ijc.28449. Marcuzzi, E., Angioni, R., Molon, B., Cali, B., 2018. Chemokines and chemokine receptors: orchestrating tumor metastasization. Int. J. Mol. Sci. 20 (1). https://doi.org/ 10.3390/ijms20010096. Martin, F., Apetoh, L., Ghiringhelli, F., 2012. Role of myeloid-derived suppressor cells in tumor immunotherapy. Immunotherapy 4 (1), 43–57. Matsubara, T., Ono, T., Yamanoi, A., Tachibana, M., Nagasue, N., 2007. FractalkineCX3CR1 axis regulates tumor cell cycle and deteriorates prognosis after radical resection for hepatocellular carcinoma. J. Surg. Oncol. 95 (3), 241–249. Mburu, Y.K., Wang, J., Wood, M.A., Walker, W.H., Ferris, R.L., 2006. CCR7 mediates inflammation-associated tumor progression. Immunol. Res. 36 (1–3), 61–72. Menten, P., Wuyts, A., Van Damme, J., 2002. Macrophage inflammatory protein-1. Cytokine Growth Factor Rev. 13 (6), 455–481.

patients. Nature 515 (7528), 563–567. Hertzer, K.M., Donald, G.W., Hines, O.J., 2013. CXCR2: a target for pancreatic cancer treatment? Expert Opin. Ther. Targets 17 (6), 667–680. Highfill, S.L., Cui, Y., Giles, A.J., Smith, J.P., Zhang, H., Morse, E., et al., 2014. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci. Transl. Med. 6 (237), 237ra267. Huang, B., Lei, Z., Zhao, J., Gong, W., Liu, J., Chen, Z., et al., 2007. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Lett. 252 (1), 86–92. https://doi.org/10.1016/j.canlet.2006.12.012. Huang, D., Ding, Y., Zhou, M., Rini, B.I., Petillo, D., Qian, C.-N., et al., 2010. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 70 (3), 1063–1071. Hwang, J., Kim, C.W., Son, K.-N., Han, K.Y., Lee, K.H., Kleinman, H.K., et al., 2004. Angiogenic activity of human CC chemokine CCL15 in vitro and in vivo. FEBS Lett. 570 (1–3), 47–51. Hyakudomi, M., Matsubara, T., Hyakudomi, R., Yamamoto, T., Kinugasa, S., Yamanoi, A., et al., 2008. Increased expression of fractalkine is correlated with a better prognosis and an increased number of both CD8+ T cells and natural killer cells in gastric adenocarcinoma. Ann. Surg. Oncol. 15 (6), 1775–1782. Imai, T., Hieshima, K., Haskell, C., Baba, M., Nagira, M., Nishimura, M., et al., 1997. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91 (4), 521–530. Inamoto, S., Itatani, Y., Yamamoto, T., Minamiguchi, S., Hirai, H., Iwamoto, M., et al., 2016. Loss of SMAD4 promotes colorectal Cancer progression by accumulation of myeloid-derived suppressor cells through the CCL15-CCR1 chemokine Axis. Clin. Cancer Res. 22 (2), 492–501. Itatani, Y., Kawada, K., Fujishita, T., Kakizaki, F., Hirai, H., Matsumoto, T., et al., 2013. Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis. Gastroenterology 145 (5), 1064–1075 e1011. Izhak, L., Wildbaum, G., Weinberg, U., Uri, W., Shaked, Y., Alami, J., et al., 2010. Predominant expression of CCL2 at the tumor site of prostate cancer patients directs a selective loss of immunological tolerance to CCL2 that could be amplified in a beneficial manner. J. Immunol. 184 (2), 1092–1101 (Baltimore, Md : 1950). Jeong, J., Kim, Y.J., Yoon, S.Y., Kim, Y.J., Kim, J.H., Sohn, K.Y., et al., 2016. PLAG (1Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol) modulates eosinophil chemotaxis by regulating CCL26 expression from epithelial cells. PLoS One 11 (3), e0151758. https://doi.org/10.1371/journal.pone.0151758. Kar, U.K., Srivastava, M.K., Andersson, A., Baratelli, F., Huang, M., Kickhoefer, V.A., et al., 2011. Novel CCL21-vault nanocapsule intratumoral delivery inhibits lung cancer growth. PLoS One 6 (5), e18758. Katoh, H., Wang, D., Daikoku, T., Sun, H., Dey, S.K., Dubois, R.N., 2013. CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell 24 (5), 631–644. https://doi.org/10.1016/j.ccr.2013.10. 009. Kawamura, M., Toiyama, Y., Tanaka, K., Saigusa, S., Okugawa, Y., Hiro, J., et al., 2012. CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patients with colorectal cancer. Eur. J. Cancer 48 (14), 2244–2251. https://doi.org/10.1016/j.ejca.2011.11.032. Kido, S., Kitadai, Y., Hattori, N., Haruma, K., Kido, T., Ohta, M., et al., 2001. Interleukin 8 and vascular endothelial growth factor – prognostic factors in human gastric carcinomas? Eur. J. Cancer (Oxford, England : 1990) 37 (12), 1482–1487. Kim, S.J., Ryu, K.J., Hong, M., Ko, Y.H., Kim, W.S., 2015. The serum CXCL13 level is associated with the Glasgow Prognostic Score in extranodal NK/T-cell lymphoma patients. J. Hematol. Oncol. 8, 49. Kirk, P.S., Koreckij, T., Nguyen, H.M., Brown, L.G., Snyder, L.A., Vessella, R.L., Corey, E., 2013. Inhibition of CCL2 signaling in combination with docetaxel treatment has profound inhibitory effects on prostate cancer growth in bone. Int. J. Mol. Sci. 14 (5), 10483–10496. Kitamura, T., Fujishita, T., Loetscher, P., Revesz, L., Hashida, H., Kizaka-Kondoh, S., et al., 2010. Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proc. Natl. Acad. Sci. U. S. A. 107 (29), 13063–13068. https://doi.org/ 10.1073/pnas.1002372107. Kitamura, T., Kometani, K., Hashida, H., Matsunaga, A., Miyoshi, H., Hosogi, H., et al., 2007. SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat. Genet. 39 (4), 467–475. Kitaura, M., Suzuki, N., Imai, T., Takagi, S., Suzuki, R., Nakajima, T., et al., 1999. Molecular cloning of a novel human CC chemokine (eotaxin-3) that is a functional ligand of CC chemokine receptor 3. J. Biol. Chem. 274 (39), 27975–27980. https:// doi.org/10.1074/jbc.274.39.27975. Ko, J., Kim, I.S., Jang, S.W., Lee, Y.H., Shin, S.Y., Min, D.S., Na, D.S., 2002. Leukotactin1/CCL15-induced chemotaxis signaling through CCR1 in HOS cells. FEBS Lett. 515 (1–3), 159–164. Kowalczuk, O., Burzykowski, T., Niklinska, W.E., Kozlowski, M., Chyczewski, L., Niklinski, J., 2014. CXCL5 as a potential novel prognostic factor in early stage nonsmall cell lung cancer: results of a study of expression levels of 23 genes. Tumour Biol. 35 (5), 4619–4628. Kumar, V., Patel, S., Tcyganov, E., Gabrilovich, D.I., 2016. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37 (3), 208–220. https://doi.org/10.1016/j.it.2016.01.004. Kuo, P.L., Chen, Y.H., Chen, T.C., Shen, K.H., Hsu, Y.L., 2011. CXCL5/ENA78 increased cell migration and epithelial-to-Mesenchymal transition of hormone-independent prostate Cancer by early growth Response-1/Snail signaling pathway. J. Cell. Physiol. 226 (5), 1224–1231. https://doi.org/10.1002/jcp.22445. Kwon, S.-H., Ju, S.-A., Kang, J.-H., Kim, C.-S., Yoo, H.-M., Yu, R., 2008. Chemokine Lkn-

213

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

preosteoblast cells in the oral squamous cell carcinoma tumor-bone microenvironment. Oncogene 32 (1), 97–105. Sanmamed, M.F., Carranza-Rua, O., Alfaro, C., Onate, C., Martin-Algarra, S., Perez, G., et al., 2014. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin. Cancer Res. 20 (22), 5697–5707. Sarvaiya, P.J., Guo, D., Ulasov, I., Gabikian, P., Lesniak, M.S., 2013. Chemokines in tumor progression and metastasis. Oncotarget 4 (12), 2171–2185. Sauer, G., Schneiderhan-Marra, N., Kurzeder, C., Kreienberg, R., Joos, T., Deissler, H., 2008. Prediction of nodal involvement in breast cancer based on multiparametric protein analyses from preoperative core needle biopsies of the primary lesion. Onkologie 31, 28–29. Schiffer, L., Worthmann, K., Haller, H., Schiffer, M., 2015. CXCL13 as a new biomarker of systemic lupus erythematosus and lupus nephritis - from bench to bedside? Clin. Exp. Immunol. 179 (1), 85–89. Schlecker, E., Stojanovic, A., Eisen, C., Quack, C., Falk, C.S., Umansky, V., Cerwenka, A., 2012. Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5dependent recruitment of regulatory T cells favoring tumor growth. J. Immunol. 189 (12), 5602–5611. https://doi.org/10.4049/jimmunol.1201018. Schott, A.F., Goldstein, L.J., Cristofanilli, M., Ruffini, P.A., McCanna, S., Reuben, J.M., et al., 2017. Phase ib pilot study to evaluate reparixin in combination with weekly paclitaxel in patients with HER-2-Negative metastatic breast Cancer. Clin. Cancer Res. 23 (18), 5358–5365. Schrader, J., 2013. The role of MDSCs in hepatocellular carcinoma–in vivo veritas? J. Hepatol. 59 (5), 921–923. https://doi.org/10.1016/j.jhep.2013.08.003. Serafini, P., De Santo, C., Marigo, I., Cingarlini, S., Dolcetti, L., Gallina, G., et al., 2004. Derangement of immune responses by myeloid suppressor cells. Cancer Immunol. Immunother. 53 (2), 64–72. https://doi.org/10.1007/s00262-003-0443-2. Shi, H., Zhang, J., Han, X., Li, H., Xie, M., Sun, Y., et al., 2017. Recruited monocytic myeloid-derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL-1beta-mediated increase in E-selectin expression. Int. J. Cancer 140 (6), 1370–1383. Shi, W.-P., Ju, D., Li, H., Yuan, L., Cui, J., Luo, D., et al., 2018. CD147 promotes CXCL1 expression and modulates liver fibrogenesis. Int. J. Mol. Sci. 19 (4). Shields, J.D., Kourtis, I.C., Tomei, A.A., Roberts, J.M., Swartz, M.A., 2010. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328 (5979), 749–752. https://doi.org/10.1126/science.1185837. Shimizu, Y., Dobashi, K., 2012. CC-chemokine CCL15 expression and possible implications for the pathogenesis of IgE-Related severe asthma. Mediators Inflamm doi: Artn 475253 10.1155/2012/475253. Silva, R.L., Lopes, A.H., Guimaraes, R.M., Cunha, T.M., 2017. CXCL1/CXCR2 signaling in pathological pain: role in peripheral and central sensitization. Neurobiol. Dis. 105, 109–116. Singh, S., Singh, R., Sharma, P.K., Singh, U.P., Rai, S.N., Chung, L.W.K., et al., 2009a. Serum CXCL13 positively correlates with prostatic disease, prostate-specific antigen and mediates prostate cancer cell invasion, integrin clustering and cell adhesion. Cancer Lett. 283 (1), 29–35. Singh, S., Singh, R., Singh, U.P., Rai, S.N., Novakovic, K.R., Chung, L.W.K., et al., 2009b. Clinical and biological significance of CXCR5 expressed by prostate cancer specimens and cell lines. Int. J. Cancer 125 (10), 2288–2295. Soler-Cardona, A., Forsthuber, A., Lipp, K., Ebersberger, S., Heinz, M., Schossleitner, K., et al., 2018. CXCL5 facilitates melanoma cell-neutrophil interaction and lymph node metastasis. J. Invest. Dermatol. Solito, S., Marigo, I., Pinton, L., Damuzzo, V., Mandruzzato, S., Bronte, V., 2014. Myeloidderived suppressor cell heterogeneity in human cancers. Year Immunol. Myeloid Cells Inflammation 1319, 47–65. Soria, G., Ben-Baruch, A., 2008. The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett. 267 (2), 271–285. Speetjens, F.M., Kuppen, P.J.K., Sandel, M.H., Menon, A.G., Burg, D., van de Velde, C.J.H., et al., 2008. Disrupted expression of CXCL5 in colorectal cancer is associated with rapid tumor formation in rats and poor prognosis in patients. Clin. Cancer Res. 14 (8), 2276–2284. Stubbs, V.E., Power, C., Patel, K.D., 2010. Regulation of eotaxin-3/CCL26 expression in human monocytic cells. Immunology 130 (1), 74–82. https://doi.org/10.1111/j. 1365-2567.2009.03214.x. Su, L., Li, N., Tang, H., Lou, Z., Chong, X., Zhang, C., et al., 2018. Kupffer cell-derived TNF-alpha promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells. Cell Death Dis. 9 (3), 323. Sugaya, M., 2015. Chemokines and skin diseases. Archivum immunologiae et therapiae experimentalis 63 (2), 109–115. Taki, M., Abiko, K., Baba, T., Hamanishi, J., Yamaguchi, K., Murakami, R., et al., 2018. Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation. Nat. Commun. 9 (1), 1685. Talmadge, J.E., Gabrilovich, D.I., 2013. History of myeloid-derived suppressor cells. Nat. Rev. Cancer 13 (10), 739–752. https://doi.org/10.1038/nrc3581. Tang, Q., Jiang, J., Liu, J., 2015. CCR5 blockade suppresses melanoma development through inhibition of IL-6-Stat3 pathway via upregulation of SOCS3. Inflammation 38 (6), 2049–2056. Toh, B., Wang, X., Keeble, J., Sim, W.J., Khoo, K., Wong, W.C., et al., 2011. Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor. PLoS Biol. 9 (9), e1001162. https://doi.org/10. 1371/journal.pbio.1001162. Trellakis, S., Bruderek, K., Dumitru, C.A., Gholaman, H., Gu, X., Bankfalvi, A., et al., 2011. Polymorphonuclear granulocytes in human head and neck cancer: enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease. Int. J. Cancer 129 (9), 2183–2193. Trellakis, S., Bruderek, K., Hutte, J., Elian, M., Hoffmann, T.K., Lang, S., Brandau, S.,

Miyazaki, H., Patel, V., Wang, H., Edmunds, R.K., Gutkind, J.S., Yeudall, W.A., 2006. Down-regulation of CXCL5 inhibits squamous carcinogenesis. Cancer Res. 66 (8), 4279–4284. Mojsilovic-Petrovic, J., Callaghan, D., Cui, H., Dean, C., Stanimirovic, D.B., Zhang, W., 2007. Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxiastimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes. J. Neuroinflammation 4, 12. Monti, P., Marchesi, F., Reni, M., Mercalli, A., Sordi, V., Zerbi, A., et al., 2004. A comprehensive in vitro characterization of pancreatic ductal carcinoma cell line biological behavior and its correlation with the structural and genetic profile. Virchows Arch. 445 (3), 236–247. Mrowietz, U., Schwenk, U., Maune, S., Bartels, J., Kupper, M., Fichtner, I., et al., 1999. The chemokine RANTES is secreted by human melanoma cells and is associated with enhanced tumour formation in nude mice. Br. J. Cancer 79 (7–8), 1025–1031. Muller, G., Hopken, U.E., Lipp, M., 2003. The impact of CCR7 and CXCR5 on lymphoid organ development and systemic immunity. Immunol. Rev. 195, 117–135. Murphy, P.M., Tiffany, H.L., 1991. Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science (New York, N Y) 253 (5025), 1280–1283. Mylonas, K.J., Turner, N.A., Bageghni, S.A., Kenyon, C.J., White, C.I., McGregor, K., et al., 2017. 11beta-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI. J. Endocrinol. 233 (3), 315–327. Nagira, M., Imai, T., Hieshima, K., Kusuda, J., Ridanpaa, M., Takagi, S., et al., 1997. Molecular cloning of a novel human CC chemokine secondary lymphoid-tissue chemokine that is a potent chemoattractant for lymphocytes and mapped to chromosome 9p13. J. Biol. Chem. 272 (31), 19518–19524. Najjar, Y.G., Rayman, P., Jia, X., Pavicic, P.G., Rini, B.I., Tannenbaum, C., et al., 2017. Myeloid-derived suppressor cell subset accumulation in renal cell carcinoma parenchyma is associated with intratumoral expression of IL1 beta, IL8, CXCL5, and Mip1 alpha. Clin. Cancer Res. 23 (9), 2346–2355. https://doi.org/10.1158/1078-0432. CCR-15-1823. Nakayama, T., Watanabe, Y., Oiso, N., Higuchi, T., Shigeta, A., Mizuguchi, N., et al., 2010. Eotaxin-3/CC chemokine ligand 26 is a functional ligand for CX3CR1. J. Immunol. 185 (11), 6472–6479 (Baltimore, Md : 1950). Nguyen, T., Lagman, C., Chung, L.K., Chen, C.H.J., Poon, J., Ong, V., et al., 2017. Insights into CCL21’s roles in immunosurveillance and immunotherapy for gliomas. J. Neuroimmunol. 305, 29–34. Ninomiya, H., Katakami, N., Osonoi, T., Saitou, M., Yamamoto, Y., Takahara, M., et al., 2015. Association between new onset diabetic retinopathy and monocyte chemoattractant protein-1 (MCP-1) polymorphism in Japanese type 2 diabetes. Diabetes Res. Clin. Pract. 108 (3), e35–37. Niwa, Y., Akamatsu, H., Niwa, H., Sumi, H., Ozaki, Y., Abe, A., 2001. Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. Clin. Cancer Res. 7 (2), 285–289. Noh, J.-R., Kim, Y.-H., Kim, D.-K., Hwang, J.H., Kim, K.-S., Choi, D.-H., et al., 2018. Small heterodimer partner deficiency increases inflammatory liver injury through C-X-C motif chemokine ligand 2-Driven neutrophil recruitment in mice. Toxicol. Sci. 163 (1), 254–264. O’Sullivan, S.A., O’Sullivan, C., Healy, L.M., Dev, K.K., Sheridan, G.K., 2018. Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia. J. Neurochem. 144 (6), 736–747. Ohta, M., Tanaka, F., Yamaguchi, H., Sadanaga, N., Inoue, H., Mori, M., 2005. The high expression of Fractalkine results in a better prognosis for colorectal cancer patients. Int. J. Oncol. 26 (1), 41–47. Okuma, A., Hanyu, A., Watanabe, S., Hara, E., 2017. p16Ink4a and p21Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis. Nat. Commun. 8 (1), 2050. Ostrand-Rosenberg, S., Sinha, P., 2009. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182 (8), 4499–4506. https://doi.org/10.4049/ jimmunol.0802740. Parker, K.H., Beury, D.W., Ostrand-Rosenberg, S., 2015. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Immunother. Cancer 128, 95–139. Persson, T., Monsef, N., Andersson, P., Bjartell, A., Malm, J., Calafat, J., Egesten, A., 2003. Expression of the neutrophil-activating CXC chemokine ENA-78/CXCL5 by human eosinophils. Clin. Exp. Allergy 33 (4), 531–537. Poschke, I., Kiessling, R., 2012. On the armament and appearances of human myeloidderived suppressor cells. Clin. Immunol. 144 (3), 250–268. Qi, X.W., Xia, S.H., Yin, Y., Jin, L.F., Pu, Y., Hua, D., Wu, H.R., 2014. Expression features of CXCR5 and its ligand, CXCL13 associated with poor prognosis of advanced colorectal cancer. Eur. Rev. Med. Pharmacol. Sci. 18 (13), 1916–1924. Qiao, B., Luo, W., Liu, Y., Wang, J., Liu, C., Liu, Z., et al., 2018. The prognostic value of CXC chemokine receptor 2 (CXCR2) in cancers: a meta-analysis. Oncotarget 9 (19), 15068–15076. Qin, C.C., Liu, Y.N., Hu, Y., Yang, Y., Chen, Z., 2017. Macrophage inflammatory protein-2 as mediator of inflammation in acute liver injury. World J. Gastroenterol. 23 (17), 3043–3052. https://doi.org/10.3748/wjg.v23.i17.3043. Qin, G., Lian, J., Huang, L., Zhao, Q., Liu, S., Zhang, Z., et al., 2018. Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis. Oncoimmunology 7 (7), e1442167. https://doi.org/10.1080/2162402X.2018. 1442167. Rudolph, B.M., Loquai, C., Gerwe, A., Bacher, N., Steinbrink, K., Grabbe, S., Tuettenberg, A., 2014. Increased frequencies of CD11b(+) CD33(+) CD14(+) HLA-DR(low) myeloid-derived suppressor cells are an early event in melanoma patients. Exp. Dermatol. 23 (3), 202–204. Sambandam, Y., Sundaram, K., Liu, A., Kirkwood, K.L., Ries, W.L., Reddy, S.V., 2013. CXCL13 activation of c-Myc induces RANK ligand expression in stromal/

214

Molecular Immunology 117 (2020) 201–215

B.-H. Li, et al.

TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13 (1), 23–35. https://doi.org/10.1016/j.ccr. 2007.12.004. Yang, L., Wang, B., Qin, J., Zhou, H., Majumdar, A.P.N., Peng, F., 2018. Blockade of CCR5-mediated myeloid derived suppressor cell accumulation enhances anti-PD1 efficacy in gastric cancer. Immunopharmacol. Immunotoxicol. 1–7. Yang, Y., Hou, J., Shao, M., Zhang, W., Qi, Y., E, S, et al., 2017a. CXCL5 as an autocrine or paracrine cytokine is associated with proliferation and migration of hepatoblastoma HepG2 cells. Oncol. Lett. 14 (6), 7977–7985. Yang, Y., Luo, B., An, Y., Sun, H., Cai, H., Sun, D., 2017b. Systematic review and metaanalysis of the prognostic value of CXCR2 in solid tumor patients. Oncotarget 8 (65), 109740–109751. Yoshimura, T., 2017. The production of monocyte chemoattractant protein-1 (MCP-1)/ CCL2 in tumor microenvironments. Cytokine 98, 71–78. Yoshimura, T., 2018. The chemokine MCP-1 (CCL2) in the host interaction with cancer: a foe or ally? Cell. Mol. Immunol. Youn, B.S., Zhang, S.M., Lee, E.K., Park, D.H., Broxmeyer, H.E., Murphy, P.M., et al., 1997. Molecular cloning of leukotactin-1: a novel human beta-chemokine, a chemoattractant for neutrophils, monocytes, and lymphocytes, and a potent agonist at CC chemokine receptors 1 and 3. J. Immunol. 159 (11), 5201–5205 (Baltimore, Md : 1950). Youn, J.I., Nagaraj, S., Collazo, M., Gabrilovich, D.I., 2008. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J. Immunol. 181 (8), 5791–5802. https://doi. org/10.4049/jimmunol.181.8.5791. Younos, I.H., Dafferner, A.J., Gulen, D., Britton, H.C., Talmadge, J.E., 2012. Tumor regulation of myeloid-derived suppressor cell proliferation and trafficking. Int. Immunopharmacol. 13 (3), 245–256. https://doi.org/10.1016/j.intimp.2012.05.002. Yu, F., Shi, Y., Wang, J., Li, J., Fan, D., Ai, W., 2013. Deficiency of Kruppel-like factor KLF4 in mammary tumor cells inhibits tumor growth and pulmonary metastasis and is accompanied by compromised recruitment of myeloid-derived suppressor cells. Int. J. Cancer 133 (12), 2872–2883. https://doi.org/10.1002/ijc.28302. Zhang, H., Li, Z., Wang, L., Tian, G., Tian, J., Yang, Z., et al., 2017a. Critical role of myeloid-derived suppressor cells in tumor-induced liver immune suppression through inhibition of NKT cell function. Front. Immunol. 8, 129. Zhang, H., Ye, Y.L., Li, M.X., Ye, S.B., Huang, W.R., Cai, T.T., et al., 2017b. CXCL2/MIFCXCR2 signaling promotes the recruitment of myeloid-derived suppressor cells and is correlated with prognosis in bladder cancer. Oncogene 36 (15), 2095–2104. https:// doi.org/10.1038/onc.2016.367. Zhang, H.Y., Ning, H.X., Banie, L., Wang, G.F., Lin, G.T., Lue, T.F., Lin, C.S., 2010. Adipose tissue-derived stem cells secrete CXCL5 cytokine with chemoattractant and angiogenic properties. Biochem. Biophys. Res. Commun. 402 (3), 560–564. https:// doi.org/10.1016/j.bbrc.2010.10.090. Zhang, Y., Lv, D.D., Kim, H.J., Kurt, R.A., Bu, W., Li, Y., Ma, X.J., 2013. A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells. Cell Res. 23 (3), 394–408. Zhao, W., Xu, Y., Xu, J., Wu, D., Zhao, B., Yin, Z., Wang, X., 2015. Subsets of myeloidderived suppressor cells in hepatocellular carcinoma express chemokines and chemokine receptors differentially. Int. Immunopharmacol. 26 (2), 314–321. Zheng, Z.-Y., Tian, L., Bu, W., Fan, C., Gao, X., Wang, H., et al., 2015. Wild-type N-Ras, overexpressed in basal-like breast Cancer, Promotes tumor formation by inducing IL8 secretion via JAK2 activation. Cell Rep. 12 (3), 511–524. Zhou, S.L., Dai, Z., Zhou, Z.J., Chen, Q., Wang, Z., Xiao, Y.S., et al., 2014. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils. Carcinogenesis 35 (3), 597–605. https://doi.org/10.1093/carcin/bgt397. Zhou, Y., Guo, F., 2018. A selective sphingosine-1-phosphate receptor 1 agonist SEW2871 aggravates gastric cancer by recruiting myeloid-derived suppressor cells. J. Biochem. 163 (1), 77–83. Ziogas, I.A., Tsoulfas, G., 2017. Evolving role of Sorafenib in the management of hepatocellular carcinoma. World J. Clin. Oncol. 8 (3), 203–213. https://doi.org/10.5306/ wjco.v8.i3.203.

2013. Granulocytic myeloid-derived suppressor cells are cryosensitive and their frequency does not correlate with serum concentrations of colony-stimulating factors in head and neck cancer. Innate Immun. 19 (3), 328–336. Tsang, J.Y.S., Ni, Y.-B., Chan, S.-K., Shao, M.-M., Kwok, Y.-K., Chan, K.-W., et al., 2013. CX3CL1 expression is associated with poor outcome in breast cancer patients. Breast Cancer Res. Treat. 140 (3), 495–504. Ueno, T., Toi, M., Saji, H., Muta, M., Bando, H., Kuroi, K., et al., 2000. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin. Cancer Res. 6 (8), 3282–3289. Umansky, V., Blattner, C., Gebhardt, C., Utikal, J., 2016. The role of myeloid-derived suppressor cells (MDSC) in Cancer progression. Vaccines 4 (4). Umansky, V., Sevko, A., 2012. Melanoma-induced immunosuppression and its neutralization. Semin. Cancer Biol. 22 (4), 319–326. Vaday, G.G., Peehl, D.M., Kadam, P.A., Lawrence, D.M., 2006. Expression of CCL5 (RANTES) and CCR5 in prostate cancer. Prostate 66 (2), 124–134. Vakilian, A., Khorramdelazad, H., Heidari, P., Sheikh Rezaei, Z., Hassanshahi, G., 2017. CCL2/CCR2 signaling pathway in glioblastoma multiforme. Neurochem. Int. 103, 1–7. Verbeke, H., Struyf, S., Laureys, G., Van Damme, J., 2011. The expression and role of CXC chemokines in colorectal cancer. Cytokine Growth Factor Rev. 22 (5–6), 345–358. Wang, C., Li, A., Yang, S., Qiao, R., Zhu, X., Zhang, J., 2018a. CXCL5 promotes mitomycin C resistance in non-muscle invasive bladder cancer by activating EMT and NF-kappaB pathway. Biochem. Biophys. Res. Commun. 498 (4), 862–868. Wang, D., Sun, H., Wei, J., Cen, B., DuBois, R.N., 2017. CXCL1 is critical for premetastatic niche formation and metastasis in colorectal Cancer. Cancer Res. 77 (13), 3655–3665. Wang, G.C., Lu, X., Dey, P., Deng, P.N., Wu, C.C., Jiang, S., et al., 2016. Targeting YAPDependent MDSC infiltration impairs tumor progression. Cancer Discov. 6 (1), 80–95. https://doi.org/10.1158/2159-8290.CD-15-0224. Wang, L., Chang, E.W.Y., Wong, S.C., Ong, S.M., Chong, D.Q.Y., Ling, K.L., 2013. Increased myeloid-derived suppressor cells in gastric Cancer Correlate with Cancer stage and plasma S100A8/A9 proinflammatory proteins. J. Immunol. 190 (2), 794–804. Wang, L., Shi, L., Gu, J., Zhan, C., Xi, J., Ding, J., Ge, D., 2018b. CXCL5 regulation of proliferation and migration in human non-small cell lung cancer cells. J. Physiol. Biochem. Wang, L., Zhang, Y.-L., Lin, Q.-Y., Liu, Y., Guan, X.-M., Ma, X.-L., et al., 2018c. CXCL1CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration. Eur. Heart J. Waugh, D.J.J., Wilson, C., 2008. The interleukin-8 pathway in cancer. Clin. Cancer Res. 14 (21), 6735–6741. Weide, B., Martens, A., Zelba, H., Stutz, C., Derhovanessian, E., Di Giacomo, A.M., et al., 2014. Myeloid-derived suppressor cells predict survival of patients with advanced melanoma: comparison with regulatory t cells and NY-ESO-1-or Melan-A-Specific t cells. Clin. Cancer Res. 20 (6), 1601–1609. Wong, Y.F., Cheung, T.H., Lo, K.W.K., Yim, S.F., Siu, N.S.S., Chan, S.C.S., et al., 2007. Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling. Oncogene 26 (13), 1971–1982. Wu, Z., Neufeld, H., Torlakovic, E., Xiao, W., 2018. Uev1A-Ubc13 promotes colorectal cancer metastasis through regulating CXCL1 expression via NF-кB activation. Oncotarget 9 (22), 15952–15967. Xie, K., 2001. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 12 (4), 375–391. Yaal-Hahoshen, N., Shina, S., Leider-Trejo, L., Barnea, I., Shabtai, E.L., Azenshtein, E., et al., 2006. The chemokine CCL5 as a potential prognostic factor predicting disease progression in stage II breast cancer patients. Clin. Cancer Res. 12 (15), 4474–4480. Yamamoto, T., Kawada, K., Itatani, Y., Inamoto, S., Okamura, R., Iwamoto, M., et al., 2017. Loss of SMAD4 promotes lung metastasis of colorectal Cancer by accumulation of CCR1+ tumor-associated neutrophils through CCL15-CCR1 Axis. Clin. Cancer Res. 23 (3), 833–844. Yang, L., Huang, J., Ren, X., Gorska, A.E., Chytil, A., Aakre, M., et al., 2008. Abrogation of

215