Semin Immunol. Author manuscript; available in PMC 2019 Feb 1.
Published in final edited form as:
PMCID: PMC5866202
NIHMSID: NIHMS928408
Neutrophils and PMN-MDSCs: their biological role and interaction with stromal cells
,1,2 ,3 ,1,2 and 1,2,3
Jie Zhou
1Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
2Key Laboratory of Tropical Disease Control, Chinese Ministry of Education, Guangzhou, China
Yulia Nefedova
3The Wistar Institute, Philadelphia, PA, USA, 19104
Aihua Lei
1Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
2Key Laboratory of Tropical Disease Control, Chinese Ministry of Education, Guangzhou, China
Dmitry Gabrilovich
1Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
2Key Laboratory of Tropical Disease Control, Chinese Ministry of Education, Guangzhou, China
3The Wistar Institute, Philadelphia, PA, USA, 19104
1Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
2Key Laboratory of Tropical Disease Control, Chinese Ministry of Education, Guangzhou, China
3The Wistar Institute, Philadelphia, PA, USA, 19104
Address for correspondence: Dmitry Gabrilovich, The Wistar Institute, 3601 Spruce Str., Rm. 118, Philadelphia, PA, 19104;
gro.ratsiw@hcivolirbagdThe publisher's final edited version of this article is available at
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Abstract
Neutrophils and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) share origin and many morphological and phenotypic features. However, they have different biological role. Neutrophils are one of the major mechanisms of protection against invading pathogens, whereas PMN-MDSC have immune suppressive activity and restrict immune responses in cancer, chronic infectious disease, trauma, sepsis, and many other pathological conditions. Although in healthy adult individuals, PMN-MDSC are not or barely detectable, in patients with cancer and many other diseases they accumulate at various degree and co-exist with neutrophils. Recent advances allow for better distinction of these cells and better understanding of their biological role. Accumulating evidence indicates PMN-MDSC as pathologically activated neutrophils, with important role in regulation of immune responses. In this review, we provide an overview on the definition and characterization of PMN-MDSCs and neutrophils, their pathological significance in a variety of diseases, and their interaction with other stromal components.
Keywords: myeloid-derived suppressor cells, neutrophils, fibroblasts, cancer, infectious diseases
1. Introduction
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of pathologically activated myeloid precursors and relatively immature myeloid cells that accumulate under many pathological conditions [1, 2]. Currently, MDSC could be further divided into two major subsets: polymorphonuclear (PMN)-MDSC and monocytic (M)-MDSC. PMN-MDSC share many morphological and phenotypic characteristics of neutrophils, whereas M-MDSC are similar to monocytes [3, 4]. In both mice and humans PMN-MDSC represent the most abundant population of MDSC. In recent years an important biological role of PMN-MDSCs has emerged. These cells have been implicated in control of immune responses and their clinical relevance has been demonstrated in cancer and other pathologic conditions. In this review, we discuss main features of PMN-MDSC vis-a-vis neutrophils and their significance in cancer and infectious diseases.
2. Neutrophil differentiation
Neutrophils are the most abundant type of granulocytes [5, 6]. The development of neutrophils occurs in the bone marrow (BM) and involves several defined steps including common myeloid progenitors, granulocyte–monocyte myeloid progenitors, myeloblasts, promyelocytes, myelocytes, metamyelocytes, band neutrophils and, finally, segmented neutrophils [7, 8]. The granules formed during neutrophil maturation serve as a reservoir of anti-microbial factors and enzymes, such as myeloperoxidase (MPO), neutrophil elastase (NE), defensins, cathelicidins and matrix metalloproteinase (MMP), which protect hosts from infections and promote the resolution of inflammation [9, 10]. After generation in the BM and brief period of circulation in peripheral blood, neutrophils migrate to the tissues. This migration is regulated by chemokines released by activated endothelial cells, fibroblasts, macrophages, and various products of microorganisms in case of infection. Apoptotic neutrophils are cleared primarily by resident tissue macrophages [6, 11, 12].
Granulocyte-colony stimulating factor (G-CSF, CSF3) has been identified as a key regulator in neutrophil development [8, 13, 14]. G-CSF receptor is expressed during granulocyte differentiation from early progenitors to mature neutrophils. However, G-CSF is not absolutely required for granulocytopoiesis as G-CSF deficient mice have around 25% of residual granulocytopoiesis and can produce fully differentiated neutrophils [15]. Other factors, such as granulocyte–macrophage-colony stimulating factor (GM-CSF, CSF2), interleukin 6 (IL-6), and c-kit ligand have been implicated in neutrophil development [16–18]. Retention of neutrophils in the BM largely depends on chemokine receptor CXCR4. Deletion of CXCR4 led to release of neutrophils from the BM into circulation [19]. In contrast, chemokine receptor CXCR2, which functions through its ligands CXCL1/CXCL2, promotes the release of neutrophils from the BM [20]. G-CSF has been shown to downregulate the expression of CXCR4 and its ligand CXCL12, leading to CXCR2/CXCL2-mediated mobilization of neutrophils into circulation [21].
3. PMN-MDSCs and neutrophils: how to distinguish these cells?
Neutrophils and PMN-MDSC have the same origin and follow the same differentiation pathway described above. They are also phenotypically similar. In mice, these cells have a phenotype of CD11b+Ly6G+Ly6Clow; in humans, they are defined as CD14−CD11b+CD15+(CD66b+) cells [2, 22]. Human neutrophils and PMN-MDSC can be separated by gradient centrifugation using 1.077 g/mL density gradient media [23]. Neutrophils are high density cells, whereas PMN-MDSC are enriched in a low-density mononuclear cell fraction. Although gradient centrifugation is actively used for evaluation of PMN-MDSC in clinical studies, there are some limitations in this method that should be considered. Specifically, a number of cells in a low-density fraction can be represented by activated neutrophils rather than PMN-MDSC. Moreover, some PMN-MDSC can be located in a high-density fraction. This may potentially lead to miscalculation of the proportion of these cells under pathological conditions. A proportion of PMN-MDSC may also be affected by mishandling of peripheral blood samples including their prolonged storage or freezing [24]. Therefore, the time before sample processing and flow cytometric analysis of PMN-MDSC should be minimized.
Despite phenotypic similarity, differences in the expression level of some surface markers have been reported between neutrophils and PMN-MDSC. Thus, mouse PMN-MDSC express higher levels of CD115 and CD244 than neutrophils [25]. However, due to heterogeneity of PMN-MDSC these markers have limited value for defining these cell populations. Recently, lectin type oxidized LDL receptor 1 (LOX-1), highly expressed on human PMN-MDSCs, has been shown to distinguish these cells from neutrophils in peripheral blood and tumor tissues of patients with a variety of cancers [26]. LOX-1 could potentially serve as a marker for identification of PMN-MDSC in cancer patients; however, more studies are needed to confirm it.
PMN-MDSC, but not neutrophils, are immunosuppressive [22, 27]. In addition to directly inhibiting T-cell function, PMN-MDSC can inhibit the activity and function of other myeloid cells and NK cells [28, 29]. In contrast, neutrophils are generally involved in the activation, regulation and effector functions of other myeloid and lymphoid cells (rev. in [5]).
PMN-MDSC and neutrophils have different molecular and biochemical characteristics [3, 22]. Quantitative proteomics of murine MDSC determined that these cells constitute a distinct myeloid population characterized by a “kinase signature” and well-defined “interactome” [30, 31]. Whole-transcriptome analysis revealed a clear difference between PMN-MDSC from tumor-bearing mice and neutrophils from tumor-free mice [25, 32]. PMN-MDSC had a higher expression of genes involved in the cell cycle, autophagy, G-protein signaling, and CREB pathway, whereas neutrophils had an elevated expression of genes associated with NF-κB signaling and lymphotoxin-β receptor signaling [25]. Further analysis confirmed that neutrophils have substantially higher basal levels of phosphorylated c-Jun, p38, JNK, and ERK1/2 than PMN-MDSC [25]. Activated neutrophils expressed significantly higher level of TNF-α as compared to PMN-MDSC [25]. In head and neck cancer patients, Brandau et al. identified a subpopulation of PMN-MDSC with reduced release of IL-8 in response to LPS as compared to mature neutrophils [33]. Some genes encoding chemokines and their receptors associated with migration were differentially expressed in PMN-MDSC and neutrophils. For instance, neutrophils had an increased levels of CXCL4 and CXCL12 and reduced expression of CCL3, CCL4, and CXCL2 as compared to PMN-MDSC [32]. PMN-MDSCs from cancer patients showed markedly reduced chemotaxis toward tumor conditioned medium and lower expression of chemokine receptors CXCR1 and CXCR2, which are necessary for neutrophil extravasation from the bloodstream and subsequent tissue infiltration [33].
A number of signaling pathways have been implicated in regulation of PMN-MDSC development and function. Activation of STAT3 was shown to be responsible for accumulation of MDSC. Therefore, upregulation of this transcription factor is considered to be a hallmark of PMN-MDSC in humans and mice [34]. Downregulation of interferon related factor (IRF)-8, a member of the IRF family, has been closely associated with PMN-MDSC expansion in mice [35–37]. It has been recently reported that tumor growth was accompanied by a selective expansion of IRF8low granulocyte progenitors with increased capability of differentiation into PMN-MDSC [38]. Up-regulation of C/EBPβ transcription factor, a member of a family of basic-region-leucine zipper transcriptional factors, was associated with MDSC expansion [39]. The most prominent factors implicated in PMN-MDSC suppressive activity on T lymphocytes so far include arginase, reactive oxygen species (ROS), and prostaglandin E2 (PGE2) [40–42]. Changes in oxidative phosphorylation and glycolysis in tumors have also been associated with MDSC function. In vitro models, increase in glycolysis rate was concurrent with an increased arginase 1 activity in MDSC [43]. Recently, tumor-infiltrating MDSC have been shown to preferentially utilize fatty acid β oxidation as a primary source of energy [44].
Endoplasmic reticulum (ER) stress response has recently emerged as an important mechanism involved in regulation of pathologic activation of MDSC and thus critical for their functions. MDSC from tumor-bearing mice and cancer patients demonstrated a significantly increased ER stress response than neutrophils and monocytes from tumor-free hosts [45]. Experimental induction of ER stress enhanced the immunosuppressive capacity of tumor-infiltrating MDSC; this effect was mediated through upregulation of ARG1, NOS2, and NOX2 expression [26]. MDSC isolated from tumors established in C/EBP homologous protein (CHOP)-deficient mice demonstrated reduced expression of phospho-STAT3 and decreased production of IL-6 and arginase 1, leading to decreased immunosuppressive activity in these cells [46]. Increased spliced X-box binding protein 1 (sXBP1), a member of another pathway of ER stress response, was observed in human LOX-1+ PMN-MDSC as compared to LOX-1− neutrophils [26]. Moreover, the induction of ER stress in neutrophils isolated from healthy donors converted them into potent immune suppressive cells [26]. Several other mechanisms of MDSC-mediated immune suppression include activation of regulatory T cells, increased expression of immune suppressive cytokines transforming growth factor β (TGF-β) and IL-10, sequestration of cysteine, and decreased expression of L-selectin by T cells among others [47].
4. Biological significance of neutrophils and PMN-MDSC interaction with stromal cells
The interaction of neutrophils with endothelial or epithelial cells has been viewed as “a double-edged sword”. On the one side, communication between these cells is essential for neutrophil migration and subsequent antimicrobial function. On the other side, their interaction causes tissue damage [20, 48].
Mature neutrophils migrate to the sites of tissue inflammation or infection through the vasculature, primarily post-capillary venules, in a well-defined sequential process referred to as neutrophil recruitment [49–52]. A clear example of the complex interaction between neutrophil and stromal cellular components such as the endothelial cells and epithelial cells were shown in . Neutrophil recruitment cascade involves multiple interactions of the neutrophil receptors with their ligands expressed on activated endothelium. The classical neutrophil recruitment cascade consists of the following steps: capturing, rolling, firm arrest, crawling, and transmigration. Transmigration occurs between endothelial cells (paracellularly) or through endothelial cells (transcellularly). While paracellular transmigration is the prevalent type, transcellular transmigration occurs in case of high intracellular adhesion molecule (ICAM)-1 expression by endothelial cells [53]. In comparison with transendothelial migration, transepithelial migration of neutrophils occurs only paracellularly. The molecular mechanisms of the neutrophil recruitment have been well defined and reviewed elsewhere [20]. During recruitment process, neutrophils release the content of their granules and produce ROS and cytokines, which together induce junction dissociation, leading to the loss of barrier integrity and consequently, to increased neutrophil transendothelial migration [54]. Neutrophil-derived proteinase 3 was found to play an important role in protecting endothelial cells from protease-activated receptor-1-induced permeability changes that occur during thrombotic and inflammatory events [55]. In contrast, heparin-binding protein released by neutrophils can induce distinct changes in endothelial cell barrier integrity through binding to proteoglycans on the cell surface [56]. Neutrophil-derived ROS and myeloperoxidase (MPO) also affect endothelial cell integrity, reducing barrier function [53, 57, 58]. It was recently shown that MPO promotes intestinal epithelial injury by inhibiting restitutive responses [59]. Thus, interactions of neutrophils with endothelial or epithelial cells during inflammation or infection can have a significant effect on the host barrier functions. There is no evidence suggesting that PMN-MDSC use different mechanisms for their interaction with endothelial and epithelial cells. In line with that, PMN-MDSC have a high level of ROS production, MPO and MMP expression, suggesting these cells possess an active machinery for transendothelial migration.
Sequential steps of neutrophil migration on endothelial and epithelial cellsA. A neutrophil migration on endothelial cells consists of the following steps: 1) binding of neutrophils to endothelial cells depends on the transient interaction of P- and E-selectins with their ligands, such as P-selection glycoprotein ligand (PSGL)-1, L-selectin and CD44; 2) rolling and slow rolling along the vessel wall depend on selectins and integrins (β2 and β1 integrins); 3) the interaction between activated integrins and their ligands (primarily ICAM-1 and ICAM-2) results in the firm neutrophil arrest on the endothelium; 4) crawling of neutrophils follows the chemokine gradient along the endothelium, which leads them to the preferential sites of transmigration; 5) transmigration of neutrophils via endothelial cell-cell junctions (paracellular transmigration) or through the endothelium (transcellular transmigration). B. For neutrophil migration across epithelia, the process contains three sequential steps: adhesion, migration, and post-migration stage. Neutrophil transepithelial migration starts with adhesion of the neutrophils to the basolateral epithelial membrane, which is supported by ligation of CD11b/CD18 on the neutrophil surface to several molecules on the epithelial surface including fucosylated glycoproteins, JAM-C. After adhesion, neutrophils crawl along the epithelial cell membrane through sequential binding to several epithelial cell surface molecules, such as CD47 (binding to SIRPα). Tight junction between neutrophil and epithelium requires binding of JAML to epithelial CAR. After neutrophils completely go through the epithelial monolayer, they adhere to the apical epithelial surface mediated by the binding of the FcR to apical antigens, binding of CD11b/CD18 to ICAM-1, and likely binding of DAF to CD97.
Interaction of neutrophils with fibroblasts has also been extensively studied under inflammatory conditions. Once activated by inflammatory stimuli, neutrophils release extracellular DNA referred to neutrophil extracellular traps (NETs)which are able to promote differentiation and function of fibroblasts leading to fibrosis [60]. In another study, neutrophil elastase has been shown to promote myofibroblast differentiation and lung fibrosis [61]. In a model of angiotensin II induced-cardiovascular injury, S100A8/A9 released by neutrophils activated cardiac fibroblasts to trigger inflammation and cardiac injury [62].
Recently, cellular network controlling PMN-MDSC migration to tumor site has been elucidated. Tumor cells inhibited release of CXCL1 and other neutrophil chemokines by carcinoma-associated fibroblasts (CAF) via production of CSF1/M-CSF[63]. This restricted migration of neutrophils and PMN-MDSC to tumor site probably evolved as a protection of tumors from infiltration by classically activated neutrophils in early stages of tumor development. Therapeutic targeting of CSF1R signaling with small molecules or antibody resulted in substantial increase in PMN-MDSC infiltration. As a result, the antitumor effect of CSF1R inhibitors was blunted. However, combination of CSF1R and CXCR2 inhibitors, which block PMN-MDSC migration to the tumor site, substantially reduced tumor progression [63]. Taken together, interactions of neutrophils with endothelial cells, epithelial cells or fibroblasts play an important role under pathological conditions and therefore, targeting key molecules that control barrier integrity and/or neutrophil function could be therapeutically beneficial ().
Neutrophils/PMN-MDSC crosstalk with stromal cells under pathological conditionsUnder inflammatory conditions, neutrophils crosstalk with endothelial cells and fibroblasts involves: (a) neutrophils release soluble factors, which on one hand protect endothelial cells like proteinase 3; on the other hand, they produce heparin-binding protein, ROS and MPO that damage the barrier integrity. (b) neutrophils release NETs or elastase to promote fibroblast differentiate into myofibroblasts, leading to lung fibrosis; (c) or they release S100A8/A9 proteins to activate cardiac fibroblasts and causes cardiac inflammation and fibrosis. PMN-MDSC, which have a high level of ROS and MPO, may also contribute to the tissue damage during their trafficking. In cancers, tumor cells inhibit the release of CXCL1 and other neutrophil chemokines by carcinoma-associated fibroblasts via production of CSF1/M-CSF, resulting in the impaired migration of neutrophils and PMN-MDSC. NETs: neutrophil extracellular traps. CAF: carcinoma-associated fibroblasts.
5. Neutrophils and PMN-MDSC in cancer
Neutrophils are traditionally considered as inflammatory immune cells and inflammation plays an important role in tumor development. High levels of neutrophils are closely associated with disease progression and poor clinical outcome. In particular, the neutrophil-to-lymphocyte ratio (NLR) and neutrophilia were independent prognostic markers in many types of cancers [64–66]. However, neutrophils were also reported to have an antitumor activity. Tumor-associated neutrophils (TANs) display plasticity and their transcriptional reprogramming could be modulated by distinct tumor microenvironment signaling [67, 68]. The roots of this controversy may lie in the nature of the cells studied. Early reports that focused on the role of mouse neutrophils in cancer did not distinguish neutrophils from PMN-MDSC. This is especially important in experiments with tumor-bearing mice where most of the neutrophils were represented by bona-fide PMN-MDSC. Unfortunately, a number of studies did not evaluate immune suppressive activity and other functions of myeloid cells and therefore, it is impossible to make a conclusion of whether these cells are either neutrophils or PMN-MDSC. Below, a role of neutrophils and PMN-MDSC in cancer is discussed.
5.1. Antitumor activity of neutrophils
There is sufficient evidence indicating that neutrophils may have antitumor activity [69, 70]. Hypoxia in the tumors can induce expression of CXCL1, CXCL2, and CXCL5 to recruit neutrophils [71]. Upregulation of the hepatocyte growth factor receptor c-MET on neutrophils by endothelial-derived TNF caused these cells to produce nitric oxide (NO), which had cytotoxic effects on cancer cells [72]. Recently, it was reported that inhibition c-MET impaired the recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions [73]. Anti-metastatic effect of neutrophils was mediated by hydrogen peroxide or thrombospondin 1, but the latter was degraded by NE and cathepsin G during inflammation [74–77]. Following antibody-mediated tumor therapy, neutrophils are activated via their Fc receptors and release mediators with direct tumoricidal activity [69]. In cancer patients, several studies demonstrated that an infiltration of tumor by neutrophils was associated with better survival [63, 78]. The number of MPO-positive neutrophils was an independent favorable prognostic factor in patients with colorectal cancer in another study; however, no significant correlation was found with CD15 expression [79]. Thus, neutrophils may have an antitumor activity. However, the vast majority of studies demonstrated a role for neutrophils in cancer promotion. PMN-MDSC, however, are always considered to exert a pro-tumorigenic effect.
5.2. Protumorigenic function of neutrophils and PMN-MDSC
Accumulating evidence has demonstrated that neutrophils play an important role in both initiation and progression of tumors [7, 80]. Deletion of CXCR2-positive neutrophils in inflammation-induced mouse models of cancer inhibited neutrophil trafficking and prevented tumor initiation [81, 82]. This was further supported by deleting neutrophils using anti-Ly6G antibodies to prevent tumorigenesis in different tumor models [81, 83–85]. Recruitment of neutrophils by PGE2 after epithelial damage could also promote tumor development [86]. Besides their role in tumor initiation, neutrophils are also involved in regulation of cancer progression, including tumor cell growth, invasion, angiogenesis, and metastasis [87, 88]. However, it is unclear whether neutrophils or PMN-MDSC were analyzed in these studies. Co-transfer of isolated tumor neutrophils (likely PMN-MDSC) and cancer cell lines increased tumor growth and angiogenesis [89]. Another study found that neutrophils (likely PMN-MDSC) can also promote tumor growth through converting senescent cancer cells into proliferating cancer cells via IL-1 receptor antagonist [90]. Neutrophils and PMN-MDSC could enhance angiogenesis through the production of MMP9, prokineticin 2 (PROK2, also known as BV8) and vascular endothelial growth factor (VEGF) [7, 91–93]. In melanoma, ultraviolet radiation led to release of high mobility group box 1 from keratinocytes, which recruited neutrophils. These neutrophils induced migration of cancer cells towards endothelial cells leading to enhanced metastasis [94]. Furthermore, neutrophils (likely PMN-MDSC) could enhance tumor metastasis by priming organ-specific pre-metastatic niche [95, 96]. For example, Yan et al. found increased neutrophil numbers in the lungs of mammary adenocarcinoma-bearing mice before tumor cell arrival and these cells produced pro-inflammatory cytokines and MMP9 [95]. Neutrophils also capture circulating cancer cells by direct interactions using the cell surface molecules or by releasing NETs, which were associated with increased formation of metastases [84, 97]. Inhibition of NETs could decrease adhesion of lung carcinoma cells and formation of metastases [98].
Characterization of PMN-MDSC in recent years demonstrated that protumorigenic activity of neutrophils could be in fact attributed to PMN-MDSC. These cells play an essential role in tumor development and progression [99, 100]. In addition to well-established immune suppressive activity, PMN-MDSC have been found to promote tumor angiogenesis through the production of soluble factors such as MMP9, BV8 and VEGF [89, 101–103]. Blockade of MDSC infiltration of tumor site resulted in the inhibition of tumor angiogenesis [104]. Furthermore, PMN-MDSC were able to acquire a proangiogenic activity after homing into tumor microenvironment or during exposure to tumor-conditioned medium ex vivo [89, 105].
PMN-MDSC were directly implicated in the promotion of tumors metastasis. In 4T1 model of breast cancer, the high level of PMN-MDSC correlated with increased bone metastasis, and co-injection of 4T1 cells and MDSC promoted lung metastasis [106]. In another study, Wei et al. found that inhibition PMN-MDSC differentiation in BM by using phytochemical polyacetylenes drastically suppresses tumor metastasis [107]. A more recent study showed that exosomes miR-126a released from MDSC induced by doxorubicin treatment promotes breast tumor lung metastasis [108]. Furthermore, MDSC are significantly increased in lungs of mice bearing mammary adenocarcinomas before tumor cell arrival [95], suggesting a role of MDSC in establishing premetastatic niche. Chemokines CXCL1, CXCL2, and CXCL5, which bind to the same receptor, CXCR2, have been shown to recruit MDSC to the tumor site [109] or to the premetastatic niche [55]. Another study also found that PMN-MDSC recruitment to the premetastatic niche relies on hypoxic tumor cell–derived monocyte chemotactic protein-1 [110].
Recently, PMN-MDSC have been shown to contribute to epithelial-mesenchymal transition (EMT) and “stemness” of tumor cells. For instance, coculture of MDSC with tumor cells induced a stem-like phenotype in tumor cells and enhanced their ability to metastasize in vivo [111]. In the ret-oncogene transgenic mouse model of spontaneous melanoma, PMN-MDSC were recruited to the tumor site and expressed hepatocyte growth factor and TGF-β. This led to EMT of primary melanoma cells [112].
5.3. Clinical relevance of neutrophils and PMN-MDSC in cancer
Despite the dual roles of neutrophils in cancer, an ever-increasing number of clinical evidence indicates NLR as negative predictor and mostly supports the notion that neutrophils promote, rather than inhibit, cancer progression [113]. In prostate cancer, NLR was identified as a predictive marker for overall survival in a cohort of 1688 patients [114]. Other studies also found an association between elevated NLR and poor survival in gastric cancer patients [115], non-metastatic renal cell carcinoma [62] and lung cancer patients [116]. A recent meta-analysis revealed that NLR is a potential prognostic biomarker in patients with ovarian cancer [117]. Collectively, these studies indicate a close association between the count of neutrophils in peripheral blood and an adverse prognosis in cancer patients. However, the contribution of PMN-MDSC to the overall pool of neutrophils, which vary between patients and cancer types, may contribute to the variability of the results.
In contrast to NLR, the prognostic and predictive power of TAN is more variable. One study suggested a positive correlation of TAN with outcome in gastric cancer patients [63] while other studies reported a negative correlation with patient outcome in renal cancer [118] and melanoma [119]. Meanwhile, there is also report showing no correlation of TAN with patient outcome in lung cancer [120]. These discrepancies may represent the result of the variability of PMN-MDSC contribution to the overall pool of TAN.
In recent years, phenotypic identification of PMN-MDSC in patients’ peripheral blood allowed for evaluation of their prognostic value. PMN-MDSC represent a reliable predictor of negative outcome and response to therapy. Studies showed an association of high PMN-MDSC numbers with poor outcomes [121–123]. PMN-MDSC frequencies correlated with the presence of tumor metastasis [124, 125]. In head and neck cancer patients, the outcome of pre-operative cetuximab treatment can be predicted by PMN-MDSC numbers, which decreased in the responder group and unchanged in non-responders [126]. Taken together, these studies highlight the potential use of PMN-MDSC in assessing the prognosis of cancer patients. However, many studies in this field still face inconsistent and arbitrary PMN-MDSC phenotyping, which impairs the use of PMN-MDSC in immune monitoring. Recent effort in clarification and unification phenotypic criteria for defining these cells in cancer should help in resolving this issue [127].
Thus, in cancer a population of neutrophils is represented by two distinct groups: bona-fide classically activated neutrophils and pathologically activated PMN-MDSC. Neutrophils may or may not display antitumor activity, whereas PMN-MDSC are universally in support of tumor progression.
6. The role of PMN-MDSCs and neutrophils in sepsis and infectious diseases
Sepsis is a systemic inflammatory response associated with uncontrolled immune activation [128, 129]. Some studies demonstrated that high levels of activated neutrophils were able to clear effectively bacteria in early sepsis [130–132] and reduced neutrophil numbers and function resulted in increased susceptibility to secondary infections [133]. However, delayed apoptosis of neutrophil is associated with tissue damage and aggravating inflammation in sepsis [134]. In addition, in polymicrobial sepsis the migration of neutrophils to the site of infection could be suppressed by TLR2 signaling via downregulation of CXCR2 [68]. The function of neutrophils in the liver during sepsis is to provide protection against bacterial dissemination by releasing NETs [135]. Parker et al. suggested that NET-associated MPO directly killed bacteria in the presence of hydrogen peroxide [136]. However, some bacteria can avoid capture and cell death by expressing nucleases degrading NETs [137].
The major function of MDSC in sepsis is immune suppression [138–141]. In a mouse model of polymicrobial sepsis, MDSC expansion was induced via MyD88 signaling and could effectively inhibit CD8+ T-cell responses [142]. Transfer of MDSC also inhibited T-cell proliferation and improved the survival rate of septic mice [143]. In these mice, PMN-MDSC defined as CD11b+CD48− cells, displayed immune suppression via inducible (i)NOS [144]. In patients with sepsis, PMN-MDSC were primarily induced by Gram-positive pathogens [145], and MDSC-mediated immune suppression was dependent on production of either ROS [145] or arginase 1 [146, 147].
During bacterial and fungal infections, neutrophils are dramatically increased in the circulation and tissues, and their reduction, due to genetic defects or chemotherapy, increases susceptibility of the host to numerous microbial infections [148–150]. However, excessive neutrophil infiltration into tissues has also been shown to result in tissue damage [151]. For instance, neutrophils displayed both protective and pathologic functions in tuberculosis (TB) caused by M. tuberculosis. Neutrophils could control the growth of M. tuberculosis [152] and their depletion resulted in an elevated severity of TB [153]. However, recent studies showed that severe TB in humans correlated with neutrophil abundance and lymphocyte deficiency [154], and excessive recruitment of neutrophils to the lungs could lead to pulmonary necrosis [155]. Depletion of neutrophils resulted in reduced lung tissue pathology in TB [156]. Mice infected with mycobacteria had an increased infiltration of lungs by MDSC. MDSC were able to phagocytose mycobacteria but did not clear this pathogen, thus acting as a shelter for intracellular bacteria [157]. Depletion of MDSC resulted in an increased T cell levels, reduced bacterial burden, and attenuated the disease [157], whereas MDSC accumulation was associated with progress and severity of TB [158]. PMN-MDSC inhibit T-cell responses in active TB. A steep drop in these cells was observed following anti-TB therapy, suggesting that they are potential biomarkers for monitoring efficacy of anti-TB treatment [159]. However, work of Chavez-Galan demonstrated that, in a mouse model of acute pleural TB, PMN-MDSC can attenuate excessive inflammation caused by infection, thus displaying a protective role [160].
Similarly, increasing evidence indicates that neutrophils play a dual role in antiviral immunity [161]. Most of the studies clearly demonstrate a protective role of neutrophils in a large array of infections [162–169]. However, excessive neutrophil activation results in production of pro-inflammatory mediators and negative impact on the host [170, 171].
Accumulation of PMN-MDSC has been reported in a variety of infectious diseases, including viral, bacterial, parasitic, and fungal infections [172, 173]. Human immunodeficiency virus type 1 (HIV-1) infection promotes MDSC expansion to facilitate viral replication [174]. Vollbrecht et al. [175] reported that untreated HIV patients had increased numbers of PMN-MDSC, which contributed to the impaired T-cell responses [176, 177]. Interestingly, Qin et al. found substantially increased proportion of M-MDSC, but not PMN-MDSC in HIV patients, which inhibited T cell responses via arginase-1 [178]. In hepatitis B virus (HBV) infected patients, PMN-MDSC expanded transiently in the acute phase of resolving HBV infection, while in persistent infection, arginase-1 positive PMN-MDSC were elevated [179]. MDSC from chronically HBV-infected patients inhibited CD8+ T cell responses through PD-1-induced IL-10 production [180]. In a mouse model of HBV infection, immune suppressive MDSC were also identified [163, 181]. An increase in immune suppressive MDSC has also been found in other viral infections, including hepatitis C virus[182], adenovirus [183] influenza A virus [184, 185] and vaccinia [186].
Bacterial infection can also cause the abundant generation of PMN-MDSC. For example, large numbers of Gram-positive and negative bacteria have been shown to induce PMN-MDSC in vitro and in vivo [187–196].
Collectively, these studies demonstrate that while neutrophils have a potent role in clearing pathogens, PMN-MDSC inhibit adaptive immune responses. The challenge is to develop approaches to translate these findings into the clinic.
7. Conclusion and perspectives
PMN-MDSC emerged as critical negative regulator of immune responses under many pathologic conditions and major partner of mesenchymal cells in promotion of tumor metastases. The distinction between PMN-MDSC and neutrophils has been debated for many years. These cells are phenotypically and morphologically similar. The main feature of PMN-MDSC that separates them from neutrophils is their immunosuppressive activity. Recently, more data have emerged indicating that these cells could be distinguished based on genomic, proteomic, and biochemical characteristics. PMN-MDSC could be considered as pathologically activated neutrophils. It appears that at any given moment patients with cancer and various chronic infections have population of classically activated neutrophils with protective functions and PMN-MDSC that promote tumor progression and immune suppression in cancer, infectious diseases and other pathologies. The therapeutic targeting of PMN-MDSC is highly promising. However, it success will depend on the development of highly selective therapeutic approaches that would shift the balance towards classical neutrophils.
Acknowledgments
This work was supported by NIH grants CA084488 and CA100062 (to DG) and CA196788 (to YN).
Abbreviation
| BM | bone marrow |
| BV8 | prokineticin 2 |
| CHOP | C/EBP homologous protein |
| EMT | epithelial-mesenchymal transition |
| ER | endoplasmic reticulum |
| G-CSF | granulocyte colony stimulating factor |
| GM-CSF | granulocyte–macrophage-colony stimulating factor |
| HBV | hepatitis B virus |
| HIV-1 | human immunodeficiency virus |
| ICAM-1(-2) | intracellular adhesion molecule-1 (-2) |
| IL-6, (IL-8, IL-10) | interleukin 6, (interleukin-8, interleukin-10) |
| IRF8 | interferon related factor 8 |
| M-CSF | macrophage colony stimulating factor |
| MDSC | myeloid-derived suppressor cells |
| MMP | matrix metalloproteinase |
| MPO | myeloperoxidase |
| NE | neutrophil elastase |
| NETs | neutrophil extracellular traps |
| NLR | neutrophil-to-lymphocyte ratio |
| NO | nitric oxide |
| NOS | nitric oxide synthase |
| LOX-1 | lectin type oxidized LDL receptor 1 |
| PGE2 | prostaglandin E2 |
| PMN | polymorphonuclear cells |
| ROS | reactive oxygen species |
| sXBP1 | spliced X-box binding protein 1 |
| TAN | Tumor associated neutrophils |
| TB | tuberculosis |
| TGF-β | transforming growth factor β |
| TNF- α | tumor necrosis factor α |
| VEGF | vascular endothelial growth factor |
Footnotes
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