Neutrophils represent the most abundant leukocyte population in human peripheral blood, and their role had long been considered restricted to their phagocytic and antimicrobial activities during the acute phase of inflammation. However, an increasing number of recent investigations had highlighted their possible impact in tumor initiation and development, and the nature of neutrophil contribution in cancer had become a hot topic in immunology. Over the years, neutrophils have been shown to display both pro-tumor and antitumor effects, emphasizing an unexpected cellular heterogeneity in cancer. In this review, we will focus on the several ‘shades’ of neutrophils in tumor initiation, growth and metastasis. In addition, we will discuss the clinical significance of tumor-associated neutrophils in humans and their potential targeting in cancer therapy.

Introduction

Cancer-related inflammation, including tumor-infiltrating inflammatory cells, has emerged as a hallmark of cancer [1]. The inflammatory response is shaped by tumor growth and has been associated with all stages of tumor development, including initiation, promotion, malignant conversion, invasion and metastasis [2].

Neutrophils are unsung ‘heroes’ in immunology and their role in health and disease has long been considered mainly limited to the acute phase of inflammation and in defense against pathogens [35]. However, neutrophils are found in many tumor types and can exert both pro-tumor and antitumor activities [68]. Therefore, neutrophils are now recognized as a key effector component of the immune system within the tumor microenvironment. Moreover, several lines of evidence demonstrated the existence of different population of neutrophils in murine tumor models and in humans. In fact, in analogy with their ‘big brothers’ macrophages and depending on environmental signals [9], tumor-associated neutrophils (TANs) presented different polarization potential [10] and were thus able to be ‘reprogrammed’ and to integrate external cues to perform complex functions. Currently, the neutrophil contribution to cancer development is predominantly considered as detrimental for the host. However, many recent reports have challenged this view, suggesting that the role played by neutrophils in oncology could be multifaceted. In this review, we will focus on the current understanding of neutrophil contribution to tumor initiation, progression and metastasis. We will also discuss the open questions concerning neutrophil heterogeneity and their clinical significance as prognostic markers for cancer patients and in cancer therapy.

Origin and recruitment of TAN

Neutrophils represent 50–70% of circulating leukocytes in humans and are generated during a process referred to as granulopoiesis that occurs in the bone marrow in a tightly regulated manner [3]. In the stem cell niche, a pool of self-renewing long-term hematopoietic stem cells gives rise to short-term hematopoietic stem cells that in turn differentiate into non-self-renewing multipotent progenitors. Subsequently, these progenitors are primed toward the myeloid lineage and further differentiate in granulocyte-monocyte progenitors [10]. The activity of granulocyte colony-stimulating factor receptor (G-CSFR) is fundamental for the differentiation of myeloid progenitors to neutrophils, as the absence of G-CSFR signal transduction leads to neutropenia and impaired neutrophil mobilization [1113]. The signal transducer and the activator of transcription 3 (STAT3) is known to regulate the steady-state production of neutrophils through the control of suppressor of cytokine signaling-3 (SOCS3) that acts as a feedback inhibitor of G-CSFR signaling [14,15]. Indeed, SOCS3-deficient bone marrow cells were hyper-responsive to G-CSF and showed prolonged STAT3 activation [15]. Accordingly, mice in which SOCS3 was deleted in hematopoietic cells developed neutrophilia, which was associated with inflammatory pathologies [15]. More recently, the transcription factor RAR-related orphan receptor γ 1 (RORC1) was also proposed as a key regulator of myelopoiesis and neutrophil maturation in cancer in response to G-CSF [16]. In particular, RORC1 was shown to suppress neutrophil maturation, thus favoring the formation of immature neutrophils with immunosuppressive activity (see below) [16].

The IL-23/IL-17 proinflammatory axis is known to induce a positive regulation of G-CSF production in steady state and during cancer progression [10,1719]. Production of IL-23 by myeloid cells is tightly regulated: for instance, tissue-resident myeloid cells (i.e. macrophages and dendritic cells) downmodulate their production of IL-23 upon phagocytosis of apoptotic neutrophils [20]. In the absence of this signal, IL-23 secretion is increased, determining the activation of IL-23R+ lymphocytes (mostly αβ T cells, γδ T cells and innate lymphoid cells) and their release of IL-17 [20]. In turn, IL-17 stimulates the increase in systemic G-CSF levels, promoting granulopoiesis and mobilization of immature neutrophils from the bone marrow [20]. In addition to IL-23, IL-1β was also involved in IL-17 production by T cells: in a model of breast cancer, the increased expression of IL-1β by macrophages has been shown to drive the production of IL-17 by γδ T cells, inducing a systemic G-CSF-dependent expansion of circulating neutrophils [21]. IL-17-dependent myeloid cell recruitment to tumor was also shown in ovarian cancer, elicited by the tumor-promoting activity of TNF-α [22].

Neutrophil recruitment to tumors has been shown to depend on several mediators [23]. First, neutrophils express high levels of the chemokine receptors CXCR1 and CXCR2, and their activation represents a potent chemotactic stimulus controlling neutrophil mobilization from the bone marrow and their recruitment into the inflamed sites [2427]. CXCR1/CXCR2 ligands (CXCL1, CXCL2, CXCL5 and CXCL8) are CXC chemokines containing the ELR motif (Glu-Leu-Arg) endowed with proangiogenic capacity and represent an important component of cancer-related inflammation. These chemokines are produced by tumor-infiltrating leukocytes, by cancer cells themselves and by cells belonging to the stromal compartment such as endothelial cells and fibroblasts [4,2830].

IL-17 has been linked with the enhanced production of CXCR2 ligands [18], and in a model of Kras-driven lung adenocarcinoma, it has been shown that constitutive IL-17 expression by lung epithelial cells increased the levels of G-CSF and CXCL1 in bronchoalveolar lavage fluid [31]. CXCL1 up-regulation correlated with the promotion of neutrophil recruitment to the tumor [31]. Besides their chemotactic properties, ELR+ CXC chemokine signaling can induce cell proliferation and was involved in cancer progression, tumor angiogenesis and metastatic potential [32].

CXCR2 has also been shown to interact with LXR ligands, or oxysterols, a class of lipidic molecules involved in cholesterol metabolism, which can be produced and released by tumor cells [33]. Indeed, oxysterol production induced neutrophil recruitment to the tumor bed, promoting neoangiogenesis and immune suppression [33].

Several other molecules were shown to mediate neutrophil trafficking in cancer, including TNF-α, hepatocyte growth factor (HGF) and CXCL6, but the responsible molecular mechanisms remain not completely understood [3437].

Neutrophils in cancer initiation, progression and metastasis

Tumor initiation and progression

Given the wide use of transplantable tumor models in cancer studies, it has been challenging to formally demonstrate the role of neutrophils in the initiation phase of tumor pathogenesis. In fact, cell line transplantation does not recapitulate the multi-stage processes of carcinogenesis occurring in humans [6,38], including the three phases of immunoediting (Elimination, Equilibrium and Escape) [39]. Indeed, transplanted cell lines have already undergone immune evasion and are often genetically identical, making them fairly different from human tumors. Moreover, the microenvironment composition of transplanted tumors is quite different from that of human tumors, in terms of matrix deposition and cellular components [6]. In this regard, chemically induced and genetically engineered tumor models have been useful to unravel the role of neutrophils in more realistic systems. For instance, in the adenomatous polyposis coli multiple intestinal neoplasia (APCmin) genetic model of intestinal carcinogenesis, the formation of neutrophil extracellular traps (NETs) has been shown to promote cancer development, through the induction of blood coagulation in a C3aR-dependent manner [40].

In the models of DMBA/TPA (7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate)-induced skin carcinogenesis and AOM/DSS (azoxymethane/dextran sodium sulfate)-induced colon carcinogenesis, CXCR2−/− mice were less susceptible to tumorigenesis compared with wild-type control, suggesting that the impairment of neutrophil mobilization and recruitment is protective for the host [41]. However, expression of CXCR2 in the tumor microenvironment is not restricted to neutrophils and was also reported in other leukocytes and in cancer cells themselves, such as pancreatic cancer cells [42,43]. Of note, it has been demonstrated that CXCR2 autocrine signaling on Kras-mutated pancreatic cancer cells promoted tumor growth and progression to pancreatic ductal adenocarcinoma [44]. In human, the prognostic significance of CXCR2 in patients with lung adenocarcinoma was related to its expression on tumor epithelial cells [45]. Consequently, the role of neurophils in primary tumor development based on studies with CXCR2-deficient mice cannot be extrapolated from these results, in contrast with their contribution to metastatic burden (see below).

Others confirmed the neutrophil pro-tumorigenic potential in colorectal cancer, showing that neutrophils were involved in tumor promotion during the early events of carcinogenesis [46,47]. However, to our understanding, those studies did not rule out the possibility of a dual role (i.e. antitumor and pro-tumor) of both circulating and tumor-associated neutrophils during different stages of tumor pathogenesis (Figure 1). For instance, Shang et al. [47] clearly demonstrated the dependency of tumor burden on the presence of neutrophils in the last phase of a model of chemically induced colorectal cancer carcinogenesis, making their conclusions more applicable to tumor progression than to tumor initiation. Similarly, Katoh et al. [46] elegantly showed that the increase in intestinal polyp number depended on the presence of CXCR2+ neutrophils, even though the earlier phases of CRC development were not investigated.

The complexity of neutrophil heterogeneity in cancer.

Figure 1.
The complexity of neutrophil heterogeneity in cancer.

Neutrophil phenotype and effector functions in cancer are determined by the integration of several factors, schematically pictured in this figure. (1) Cytokines, growth factors and other soluble mediators present within the tumor microenvironment and in peripheral tissues can skew neutrophil polarization toward N1-like or N2-like activation state. These factors are produced by hematopoietic, stromal and tumor cells. (2) Different neutrophil phenotypes have been reported according to the stage of tumor development. Indeed, at the early stage of tumor growth, neutrophils may display antitumor properties, through stimulation of T cells, while tumor progression is suggested to promote an immunosuppressive phenotype in neutrophils. (3) Tissue-specific features have been characterized in mouse and human neutrophils. For instance, while bone marrow-derived neutrophils are phenotypically immature and possess limited effector functions, TANs display a terminally differentiated phenotype and a wide range of effector functions. (4) Typical neutrophil features and activities, such as the formation of granules and migratory capacity, are gradually acquired during granulopoiesis. Different molecules produced during cancer-related inflammation (e.g. G-CSF, ELR+ chemokines) are involved in maturation and/or mobilization of neutrophils.

Figure 1.
The complexity of neutrophil heterogeneity in cancer.

Neutrophil phenotype and effector functions in cancer are determined by the integration of several factors, schematically pictured in this figure. (1) Cytokines, growth factors and other soluble mediators present within the tumor microenvironment and in peripheral tissues can skew neutrophil polarization toward N1-like or N2-like activation state. These factors are produced by hematopoietic, stromal and tumor cells. (2) Different neutrophil phenotypes have been reported according to the stage of tumor development. Indeed, at the early stage of tumor growth, neutrophils may display antitumor properties, through stimulation of T cells, while tumor progression is suggested to promote an immunosuppressive phenotype in neutrophils. (3) Tissue-specific features have been characterized in mouse and human neutrophils. For instance, while bone marrow-derived neutrophils are phenotypically immature and possess limited effector functions, TANs display a terminally differentiated phenotype and a wide range of effector functions. (4) Typical neutrophil features and activities, such as the formation of granules and migratory capacity, are gradually acquired during granulopoiesis. Different molecules produced during cancer-related inflammation (e.g. G-CSF, ELR+ chemokines) are involved in maturation and/or mobilization of neutrophils.

The functionally dynamic nature of neutrophils in pathology appears more relevant in light of other recent reports, showing the active contribution of neutrophils to the very early phases of cancer development in rather unexpected forms. For instance, in a mouse model of uterine epithelial carcinogenesis, neutrophils have been shown to be protective through their promotion of cancer cell detachment from the basement membrane [48]. Indeed, neutropenic mice displayed earlier tumor occurrence and faster malignant transformation compared with immunocompetent controls [48]. In this specific model, CXCR2 activation mediated neutrophil recruitment to the inflamed site, in response to the up-regulation of CXCR2 ligands induced by hypoxia. Of note, the authors found a prognostic correlation in humans between neutrophil density and overall survival by in silico analysis.

As for tumor initiation, most papers studying neutrophils in tumor progression largely point toward a pro-tumorigenic view of this cell type. Nevertheless, several reports showed the opposite activity, even using transplantable tumor models. While some contrasting results may simply depend on context-specific mechanisms (i.e. the opposite effects of TNF-α-dependent neutrophil activation [22,36]), other differences might be attributable to distinct neutrophil functions at different time points of tumor progression (Figure 1). This would be in keeping with a more dynamic view of neutrophil functions, in which antitumor mechanisms, such as the cytotoxic activity through the production of reactive oxygen species (ROS), are predominant in the early phases of tumor progression, while other features, such as the production of arginase 1 or matrix metalloprotease-9, have pro-tumor activities [29,49,50]. The hypothesis of a dual role for neutrophils in cancer at different time points of tumor progression is now supported by a growing body of literature, deriving from both human and murine studies [5054]. For instance, Liu et al. [51] demonstrated that tumor-infiltrating neutrophils at early stages of tumor progression were able to reduce the production of IL-17 by T cells and to promote the cytotoxic functions of CD8+ T cells, resulting in the early control of tumor growth. A functional comparison between neutrophils isolated from early- and late-stage tumor-bearing mice evidenced a progressive loss of several activation markers [i.e. CD54 or ICAM-1 (intercellular adhesion molecule 1)] and tumor-suppressive features (i.e. production of ROS and TNF-α) during the course of tumor progression [50]. The authors validated these assumptions by in vivo depletion of neutrophils in different time frames of tumor growth.

Metastasis

As mentioned above, for tumor initiation and tumor progression, the contribution of neutrophils in the formation of metastasis is also controversial, as both prometastatic and antimetastatic activities have been described [10]. The accumulation of neutrophils in tissues distant from the primary tumor was shown to favor metastasis in different models, such as the genetic model of spontaneous breast cancer PyMT-MMTV. In this model, neutrophils were shown to precede tumor-disseminating cells in the lung, suggesting a role for neutrophils in the formation of the metastatic niche [28,5558]. The growth factor G-CSF was involved in the mobilization of neutrophils in the pre-metastatic niche [59]. Kowanetz et al. showed that tumor-derived G-CSF promoted neutrophil colonization of lungs before tumor cell dissemination. Besides promoting the expansion and recruitment of neutrophils, G-CSF was reported to induce the expression of Bv8 in neutrophils, promoting tumor angiogenesis and cell migration [5961]. Moreover, other neutrophil-derived molecules (i.e. S100A8 and S100A9) were suggested to modify lung microenvironment, contributing to the formation of the pre-metastatic niche [59]. The early neutrophil accumulation in the pre-metastatic lung and their influence on the formation of metastases were also confirmed by recent investigations [21,55].

In a genetic model of pancreatic cancer, CXCR2−/− mice did not show altered primary tumor growth compared with wild-type mice, but displayed a significant reduction in metastasis formation [43]. Importantly, neutrophil-depleted animals phenocopied CXCR2-deficient mice in terms of tumor growth, while a specific deletion of CXCR2 in pancreatic tumor cells had no effect on survival or metastasis formation, suggesting that neutrophils were specifically responsible for metastatic burden in the liver [43].

In a syngeneic orthotopic mammary cancer model, unidentified factors derived from hypoxic tumor cells promoted the recruitment of granulocytic cells in the lung pre-metastatic niche, favoring the formation of metastasis [56]. Others showed that the interaction between the β2 integrin expressed on neutrophils and ICAM-1 on melanoma cells facilitated the passage of cancer cells through the circulation and increased the occurrence of metastasis in the lung [28]. In a model of breast cancer, a recent investigation identified neutrophils as key drivers of metastatic establishment within the lung pre-metastatic niche [55]. Indeed, despite their low frequency in the primary tumor, neutrophils accumulated in the pre-metastatic lung, and neutrophil-deficient mice displayed reduced lung metastasis [55]. Neutrophils infiltrating the pre-metastatic lung secreted high levels of the lipidic mediator leukotriene B4 (LTB4), a product of 5-lipoxygenase (Alox5). LTB4 acts on cancer cells expressing LTB4 receptor, determining the generation of a heterogeneous cancer cell population, endowed with high metastatic potential [55]. Of note, depletion of Alox5 in the immune cell compartment reduced cancer cell metastatic potential in vitro and abolished the formation of metastases in vivo [55].

The signaling of TGF-β in neutrophils, a critical mediator of their polarization [29], was involved in metastasis formation [62]. In an orthotopic model of breast cancer, TGF-β produced by myeloid cells, T cells and tumor cells acted on CD11b+ Ly6C+ monocytes and CD11b+ Ly6G+ neutrophils to induce an immunosuppressive phenotype characterized by the expression of iNOS and arginase 1 [62]. Moreover, TGF-βRII signaling on myeloid cells was shown to be fundamental for lung metastasis formation, and reconstitution with wild-type CD11b+ Ly6G+ neutrophils (but not with Ly6C+ monocytes), and was sufficient to increase metastatic burden [62]. Importantly, these investigations did not show any pro-tumor effect of neutrophils regarding the growth of the primary tumor, suggesting that neutrophils may have different activities in controlling primary tumor growth and metastatic dissemination.

NETs have also been shown to promote the seeding of circulating cancer cells in the pre-metastatic niche, and in vivo treatment with DNAse, which degrade NETs, was able to reduce cancer cell dissemination in the metastatic liver [63]. More recently, NETs' involvement in metastasis has also been reported for breast cancer cell dissemination in the lung. Indeed, Park et al. [64] showed that tumor cell-derived G-CSF promoted NET formation by neutrophils and facilitated lung metastasis. Both reports demonstrated the strong dependence of metastasis formation on the presence of NET-associated proteolytic enzymes (i.e. elastase and cathepsin G) [63,64].

In contrast with these prometastatic activities of neutrophils, other studies showed that neutrophils displayed antimetastatic functions [36,52,65,66]. For instance, depletion of neutrophils in mice orthotopically implanted with breast cancer cells increased lung metastasis [52]. In this model, tumor-entrained neutrophils were accumulated in the pre-metastatic lung and displayed a H2O2-dependent cytotoxic activity against tumor cells. Accumulation of neutrophils in the pre-metastatic lung and their subsequent activation were mediated by G-CSF and CCL2 [52]. On the same line, it has been shown by others that neutrophils possess anti-metastatic activities through the expression of thrombospondin-1 and of the proto-oncogene MET [36,66]. In particular, the stimulation of neutrophils with tumor-derived TNF-α induced MET expression. In turn, MET signaling triggered by HGF, which is present in the tumor microenvironment, endowed neutrophils with antitumor cytotoxic activity against tumor cells [52]. Accordingly, deletion of MET in hematopoietic cells and specific blockade of MET on neutrophils increased the number of metastasis in mice [36].

An overview of neutrophil heterogeneity in cancer

Nomenclature and identification of neutrophil subsets

The concept of neutrophil heterogeneity dates back to the 1920s [67], and its causes and biological meaning have been object of numerous investigations ever since [68]. Both human and murine neutrophils display high morphological and functional varieties, depending on their maturation state, tissue of origin and physio-pathological conditions [69].

In cancer, the first demonstration of a dual polarization state for neutrophils was given by Fridlender et al. [29]. In that seminal paper, the terms N1 and N2 were introduced, referring to antitumor and pro-tumor activation state, respectively. TGF-β, abundantly produced in tumor-bearing hosts, was responsible for the N1 to N2 transition. Later on, other molecular modulators of neutrophil polarization were proposed, such as type I IFNs and G-CSF [70,71]. Moreover, ER (endoplasmic reticulum)-stress-related proteins have been shown to induce an immunosuppressive phenotype in human neutrophils isolated from cancer patients [72,73].

N2-polarized neutrophils closely resemble immunosuppressive granulocytes, also known as granulocytic myeloid-derived suppressor cells (g-MDSCs), a population of neutrophils characterized by their ability to inhibit T-cell activation ex vivo [6], and are phenotypically identical with normal neutrophils. In human, g-MDSCs were identified as CD15+ CD66b+ CD33dim HLA-DR− [68], often making them undistinguishable from non-immunosuppressive neutrophils [74]. To avoid any possible ambiguity in cell classification, efforts are currently being made to standardize MDSC identification strategy [75], particularly by flow cytometry [76].

Maturation degree was suggested to be related to the immunosuppressive potential of neutrophils [77,78]. Indeed, several morphological features of immunosuppressive granulocytes are typical of immature cells (i.e. band nuclei, low expression of CD11b and CD16). Moreover, in inflammatory conditions, such as cancer, a high number of immature granulocyte precursors are released from the bone marrow into the circulation, through a mechanism known as ‘emergency granulopoiesis’, and these cells are deemed with immunosuppressive potential [16,79].

Different buoyancy in density gradients was exploited to separate the total neutrophil population into low-density neutrophils (LDNs) and normal-density neutrophils (NDNs) from peripheral blood, in both humans and mice [72,8082]. For the sake of clarity, we support the nomenclature according to which neutrophils migrating to the granulocytic fraction of density gradient should be referred to as NDNs and not high-density neutrophils (HDNs), as it was done in the past [68,69]. As recently reviewed [68], LDNs in human and mouse peripheral blood include immunosuppressive (g-MDSCs), proinflammatory (referred to as low-density granulocytes) neutrophils and immature granulocytic precursors. On the other hand, the NDN fraction can contain both mature and immature cells, with either immunosuppressive or proinflammatory capacity [70,83] (see Table 1).

Table 1
Different denominations, functions, localization and phenotypic characteristics of neutrophils in cancer
DenominationPro-/antitumor functionSpeciesTissue localizationNucleus shapeDensityExpression markerInducing stimulusMolecular and/or cellular functionsRef.
N2 neutrophils PMN-MDSCs Pro-tumor Human PB Banded or segmented Normal or low CD10 ND CD18-dependent arginase release [81
Human PB, tumor Banded Low LOX-1 ER stress ROS and arginase production [72
Mouse BM, PB, tumor NA NA Ly6G G-CSF ROS and Bv8 production [59,71,112
Human, mouse PB Banded Low CD11bint FSChigh TGF-β Inhibition of T-cell proliferation [82
N1 neutrophils TEN Antitumor Human, mouse PB, tumor Segmented NA CD54 IFN-β NET-mediated tumor cell cytotoxicity [70
Mouse Tumor Segmented NA CD54 TGF-β blockade ROS-mediated tumor cell cytotoxicity, T-cell stimulation [29
Human Tumor Segmented NA CD54, HLA-DR, CD86, CD14, CCR7 IFN-γ, GM-CSF Stimulation of T-cell cytotoxic activities [53,54
Mouse PB NA Normal Ly6G CCL2 ROS-mediated tumor cell cytotoxicity [52
DenominationPro-/antitumor functionSpeciesTissue localizationNucleus shapeDensityExpression markerInducing stimulusMolecular and/or cellular functionsRef.
N2 neutrophils PMN-MDSCs Pro-tumor Human PB Banded or segmented Normal or low CD10 ND CD18-dependent arginase release [81
Human PB, tumor Banded Low LOX-1 ER stress ROS and arginase production [72
Mouse BM, PB, tumor NA NA Ly6G G-CSF ROS and Bv8 production [59,71,112
Human, mouse PB Banded Low CD11bint FSChigh TGF-β Inhibition of T-cell proliferation [82
N1 neutrophils TEN Antitumor Human, mouse PB, tumor Segmented NA CD54 IFN-β NET-mediated tumor cell cytotoxicity [70
Mouse Tumor Segmented NA CD54 TGF-β blockade ROS-mediated tumor cell cytotoxicity, T-cell stimulation [29
Human Tumor Segmented NA CD54, HLA-DR, CD86, CD14, CCR7 IFN-γ, GM-CSF Stimulation of T-cell cytotoxic activities [53,54
Mouse PB NA Normal Ly6G CCL2 ROS-mediated tumor cell cytotoxicity [52

Abbreviations: PB, peripheral blood; PMN, polymorphonuclear; MDSC, myeloid-derived suppressor cell; BM, bone marrow; TEN, tumor-entrained neutrophil; ROS, reactive oxygen species; ER, endoplasmic reticulum; NET, neutrophil extracellular trap; NA, not assessed.

Of note, the transition from NDN to LDN (but not the opposite) was shown in circulating neutrophils from tumor-bearing hosts, implying a temporal directionality in the acquisition by neutrophils of immunomodulatory properties during tumor growth [82].

Markers of immunosuppressive neutrophil populations

In addition to this complex picture, the definition of neutrophil subsets might even be more entangled by the high variability among individuals and among pathologies. Thus, investigators have tried to identify markers that might univocally discriminate between suppressive and non-suppressive neutrophils. In this regard, CD10, a marker acquired during the last stages of neutrophil maturation, has been shown to identify a population of immunosuppressive neutrophils [81]. Differently from previous reports where immunosuppressive neutrophils presented an immature phenotype [84], in this study the immunosuppressive granulocytic fraction was composed of mature neutrophils (CD66b+ CD10+) present in both LDN and NDN fractions [81]. However, these findings are in agreement with the work of other groups [85]. In contrast, CD10− CD66b+ immature LDNs displayed T-cell-stimulating properties, being able to promote T-cell proliferation and IFN-γ production [81]. In patients with non-small cell lung cancer (NSCLC), a study showed that the scavenger receptor lectin-type oxidized LDL receptor 1 (LOX-1) was more expressed in the immunosuppressive LDN fraction compared with NDNs, which, in contrast, did not display any capacity of modulating T-cell activation [72]. Importantly, LOX-1 expression was induced only in LDNs isolated from cancer patients, and it was not detectable in healthy donor neutrophils. In line with a previous report in which granulocyte immunosuppressive activity depended on the ER stress-related transcription factor Chop [73], LOX-1 was shown to be up-regulated in neutrophils upon experimental induction of ER stress [72].

Taken together, these recent reports suggest that neutrophil's immunosuppressive ability depends more on context-specific factors rather than on their maturation stage or buoyancy properties (see Table 1). Moreover, it is relevant to consider that experimental cell isolation and manipulation can artifactually modify neutrophil cell density [86], and thus interfere with further identification and classification. To avoid such issues, it has been proposed to isolate neutrophils (or neutrophil subsets) from total blood, regardless of granulocyte buoyancy properties [68].

Neutrophil functions during tumor progression: the immunosuppressive switch

The divergent functions displayed by neutrophils at different stages of tumor growth (i.e. early or late) could explain at least part of the contrasting reports present in the past and present literature, showing either pro-tumor or antitumor activities for neutrophils [6]. Eruslanov et al. [54] demonstrated that TANs isolated from early-stage NSCLC patients presented a wide range of co-stimulatory molecules and were able to stimulate the proliferation of CD4+ T cells and CD8+ T cells. In a recent paper from the same group, it was shown that early-stage NSCLC biopsies harbored a ‘hybrid’ subset of TANs, characterized by the expression of prototypical antigen-presenting cell(APC) markers such as HLA-DR and CD86 [53]. The origin of this subset, present only in tumor tissue but not in periphery, was addressed. Importantly, immature bone marrow neutrophils, but not mature circulating neutrophils, were able to acquire APC features and concomitantly T-cell-stimulating capacity in response to GM-CSF and IFN-γ present in the tumor microenvironment [53].

In mice, the concept of the ‘immunosuppressive switch’ was exemplified for both TANs and circulating neutrophils, in models of breast cancer, lung cancer and mesothelioma [50,82]. The authors postulated that the immunosuppressive factors TGF-β, increasingly produced over the course of tumor progression, could induce neutrophil transition from a tumor-suppressive phenotype into a tumor-promoting phenotype [82]. It is noteworthy that even if the immunosuppressive switch virtually applies to every white blood cell subset [1], neutrophils have been overlooked until some years ago probably because of their relatively short lifespan. However, while it is true in homeostatic conditions [87], cancer-related inflammation can significantly prolong neutrophil lifespan [54].

Neutrophil heterogeneity in tissues

The majority of the human studies reviewed here focus on peripheral blood neutrophils (mainly because of practical and ethical issues), while the immunosuppressive activity in murine models is usually performed on splenic or bone marrow-derived neutrophils. However, it is now becoming clear that TANs display distinct phenotypic and functional features (i.e. higher expression of maturation and activation markers), compared with their circulating and bone marrow counterparts.

Spleen was believed to be an important extramedullary proliferation site for g-MDSC [88] and was shown to be essential for their expansion and recruitment into the growing tumor in mice [89]. Nevertheless, the contribution of spleen-derived granulocytes to the overall TAN immunomodulatory functions is still a matter of debate [6]. Moreover, differently from canonical granulocytes, splenic neutrophils have been described to exert peculiar functions, such as B-cell activation in the spleen marginal zone [90].

Adding up to the already discussed heterogeneity, previous investigations revealed that neutrophils are able to perform reverse transendothelial migration, a process that may control the exacerbated neutrophil extravasation [91]. Consequently, peripheral blood neutrophils may be composed of a mixture of ‘naive’ and tissue-experienced neutrophils.

Finally, it is known that murine and human neutrophils are different under many aspects, such as their relative frequency in blood, their granule composition, the expression of Fc receptors and the expression of soluble mediators (e.g. IL-10) [6]. Furthermore, human neutrophils do not express Ly6G antigen, which uniquely identifies neutrophils in mice. This complicates the translation into a human setting of data derived from murine studies.

In conclusion, some issues concerning neutrophil heterogeneity remain unsolved, including the existence of a common precursor for g-MDSCs and non-immunosuppressive neutrophils, or the biological relevance of buoyancy alterations in neutrophil subsets. Moreover, even though important results have been obtained in this regard [53,70,72,81], it is still premature to label any neutrophil subset with a pro-tumor activity or an antitumor activity only relying on phenotypic characterization.

Prognostic significance of neutrophils in cancer and therapy strategies

Neutrophils as prognostic markers in cancer

A high number of circulating neutrophils in cancer patients have been associated with a poor prognosis. In particular, the ratio between neutrophil and lymphocyte frequencies (neutrophil-to-lymphocyte ratio, NLR) in peripheral blood correlated with faster tumor progression and reduced patient survival in the majority of solid tumors [92]. NLR measurements are easily obtained in clinical practice. However, high variability in NLR is suspected to be observed in patients over time [10]. For this reason, multiple NLR measurements of the same patient over tumor progression could be more accurate.

Compared with NLR, the clinical significance of neutrophil density within tumors is more debated. In human tumors, neutrophils represent a significant component of the infiltrating immune cells in several tumor types such as the liver, head and neck, kidney, and lung [6,35,9395]. For instance, in NSCLC patients, neutrophils have been identified as the dominant immune cell type infiltrating the tumor bed [96]. In most cases, the clinical significance of neutrophil infiltration has been associated with a poor prognosis [35,9395]. However, there have been controversial reports concerning the prognostic significance in other cancer subtypes, such as in gastric cancer and colorectal cancer. These discrepancies are likely due to different methodological approaches used for the identification of neutrophils and to selection of patients datasets [97]. In this regard, our group recently proposed to adopt CD66b as a neutrophil-specific marker to be used for TAN quantification in paraffin-embedded colorectal tumor biopsies [98]. Our study revealed a survival advantage for patients with neutrophil-rich tumors at stages I–IV of colorectal cancer, and a multivariate analysis showed that the prognostic significance of neutrophils was influenced by 5-fluorouracil (5-FU)-based chemotherapy treatment [98]. Importantly, infiltration of neutrophils was associated with poor prognosis in untreated patients and with better response to chemotherapy, suggesting a dual clinical significance for neutrophils in colorectal cancer that may help identify patients likely to benefit from 5-FU-based chemotherapy [98]. Moreover, a recent study showed that TAN infiltration was associated with a survival benefit in gastric cancer patients receiving 5-FU-based chemotherapy [51]. The correlation of TAN infiltration with better prognosis in colorectal cancer patients was recently confirmed by another group, which extended the analysis to CD8+ T cells. Intriguingly, it was shown that TAN colocalized with effector CD8+ T cells and improved their clinical significance [99]. In a recent study with a large cohort of CRC patients, the authors reported a positive correlation between high neutrophil infiltration at the tumor front and better prognosis, specifically in the early stages (I–II) of tumor progression [100]. The association between neutrophils and chemotherapy is also supported by a preclinical study in which neutrophil depletion significantly impaired the response to doxorubicin in models of mammary carcinoma and fibrosarcoma [101]. However, different studies reported that neutropenia, which is induced during chemotherapy, was associated with increased survival in patients with different cancer subtypes [10]. Therefore, whether neutrophils play a beneficial or detrimental role in chemotherapy remains a debated issue.

Clinical significance of TANs in cancer therapy

Contrasting data about the beneficial or detrimental role of neutrophils were also reported in relation to radiation therapy. For instance, Deng et al. showed that in a model of subcutaneous colon cancer, neutrophil depletion enhanced radiotherapy efficacy. On the other hand, neutrophils were shown to play a key role in response to radiation therapy by the production of ROS and the induction of apoptosis in tumor cells [102,103].

Given that TAN infiltration has been associated with bad prognosis in several cancer types, it has been tried to hinder tumor growth by interfering with neutrophil homing into the tumor bed. For instance, in a preclinical model of pancreatic cancer, the inhibition of CXCR2 signaling with a pepducin peptide, which inhibits CXCR2 signaling by interfering with its ability to couple to intracellular signal transduction molecules, decreased the number of myeloid cells in the pre-metastatic liver and was associated with reduced metastasis number and increased overall survival [43]. Interestingly, CXCR2 inhibition could increase the number of intratumor CD3+ T cells, while the combined inhibition of CXCR2 signaling and PD-1 in tumor-bearing mice significantly extended host survival [43]. As mentioned earlier, however, CXCR2 expression in human tumors is not limited to neutrophils. In fact, CXCR2 signaling can intrinsically elicit a proliferative response in cancer cell themselves, leading to pro-tumor activity [44,104]. This suggests that the beneficial effect of CXCR2 inhibition might not be restricted to the reduction in neutrophil homing to the tumor. In human, a clinical trial in phase Ib examined the safety and pharmacokinetics of escalating doses of reparixin, a CXCR1 and CXCR2 inhibitor, in combination with paclitaxel in women with HER-2-negative metastatic breast cancer [105]. This clinical trial revealed no serious adverse events and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles [105]. Interestingly, the higher dose of reparixin induced a decrease in neutrophil count in 13% of patients and was selected for further study in a randomized phase II trial (NCT02370238) [105].

IL-17 may also represent a putative target to modulate neutrophil trafficking to tumors. A recent study showed that in a genetic model of Kras mutation-driven lung adenocarcinoma, the forced overexpression of IL-17A caused neutrophil accumulation in lungs and negatively affected anti-PD-1 therapy. Interestingly, TAN frequency within a restricted cohort of NSCLC patients was inversely correlated with T-cell infiltration [31]. Besides the limitations of this study (i.e. IL-17A levels in mice are not physiological and the tumor stage for NSCLC patients was not reported), it is likely that, to some extent, neutrophils can modulate adaptive immunity in lung cancer and even influence immunotherapeutic response [31]. In this regard, in NSCLC patients, neutrophils were the most abundant immune cell type in the tumor bed and a negative correlation was reported between TAN and CD8+, CD4+ Th1 and CD4+ Th17 cell infiltration. In contrast, the amount of CD4+ regulatory T cells was not influenced by the presence of neutrophils [96]. In NSCLC patients, clinical evidence indicating a predictive significance of TAN in response to therapy with immune checkpoint blockade (anti-CTLA-4 or anti-PD-1) is lacking. In contrast, recent reports showed that the preoperative NLR had a predictive value in relation to the response to anti-PD-1 therapy [106108]. Indeed, a high NLR was associated with impaired response to therapy and poor patient outcomes. Given the high level of neutrophil infiltration in the lung of NSCLC patients, it would be important to determine whether neutrophils are actively involved in immunotherapy failure, possibly analyzing TAN phenotype alterations during therapy in perspective studies. Interestingly, a recent study showed that c-MET pharmacological inhibition hampered activated neutrophil recruitment in different cancer models, including lung adenocarcinoma (LLC), leading to increased efficacy of anti-PD-1 therapy [109].

In gastric cancer, TANs strongly expressed PD-L1 and were associated with disease progression and reduced patient survival [110]. Tumor-derived GM-CSF induced PD-L1 expression on neutrophils, suppressing T-cell-dependent immune response; accordingly, blockade of neutrophil-associated PD-L1 inhibited tumor growth [110]. Of note, this was not the first study to report PD-L1 expression on neutrophils, as it was shown also in HIV patients where it was associated with immunosuppressive activity toward CD3+ T cells [111].

Preclinical studies showed that neutrophil-targeting approaches might be useful to limit the ‘angiogenic switch’ and the formation of metastases. For instance, treatment of VEGF-resistant tumors with anti-G-CSF or anti-Bv8 was shown to reduce tumor angiogenesis and growth, suggesting that neutrophil may be involved in refractoriness to anti-VEGF treatment [112]. IL-17 signaling pathway in the microenvironment was involved in the resistance to VEGF blockade by G-CSF induction and consequential mobilization of proangiogenic neutrophils in the tumor [113]. Indeed, anti-VEGF treatment, combined with either G-CSF or IL-17 blockade, showed therapeutic synergy [113,114]. Finally, neutrophils were shown to support lung metastasis dissemination by secretion of LTB4, a product of the Alox5 pathway [55]. Interestingly, in vivo treatment with the specific Alox5 inhibitor zileuton of tumor-bearing mice reduced the metastasis formation, without affecting the growth of the primary tumor [55]. In human breast cancer, infiltration of neutrophils was associated with poorer prognosis and LTB4 receptor was detected within the metastatic lung [55].

General conclusions

The growing body of evidence linking neutrophils to several aspects of cancer pathogenesis put on the spotlight an unanticipated complex picture regarding the role and characteristics of neutrophils in cancer, such as the dependence of their phenotypes on the environmental conditions. This complexity was reported in all aspects treated in this review, starting from tumor initiation and progression to cancer metastasis and clinical relevance. Similarly to T cells and macrophages, it has been complicated to uniformly define the population of tumor-associated neutrophils and to classify them as host-protective or tumor-promoting cells. An additional issue regards antibody-mediated neutrophil depletion, which is the most common approach to demonstrate neutrophil involvement in tumor (and other) murine models. This procedure has been shown to be poorly efficient in long-term experiments [52,115], as the mechanisms leading to cell elimination are gradually impaired. Consequently, in tumor models lasting more than 2–3 weeks, neutrophil-depleted animals might actually present circulating or even tissue-infiltrating neutrophils without detecting them with standard phenotyping procedures. Indeed, long-term treatments with α-Ly6G antibody (1A8) can mask Ly6G antigen expression on neutrophil cell surface [115], thus interfering with correct data interpretation.

It is now becoming clear that several subsets of neutrophils with different effector functions exist in human and mice cancer. The diversity, the abundance and the biologic activities of those different subsets may be dependent on the organism's pathophysiological state but also on tissue-specific factors. Therefore, it is now challenging to define these different populations and to identify robust and reliable methods in order to discriminate them in tissues. Additionally, it would be important to determine whether and how those subsets are related to each other, for instance from a developmental point of view. It is interesting to point out that several unanswered questions asked more than 30 years ago, and related to neutrophil diversity still remain, at least partially, without a clear explanation. Nevertheless, important steps forward have been, and continue to be, taken, thanks to recent technological advancements such as deep immunophenotyping and single-cell based ‘omics’ studies [10,67].

In human, the clinical significance of tumor-associated neutrophils in determining patient prognosis and in predicting treatment outcome has been proposed. Targeting the immune system rather than, or in addition to, cancer cells is now a reality and neutrophils have been acknowledged as an important component of the tumor microenvironment. With this premises, a future therapeutic approach targeting neutrophil subpopulations may represent a step forward toward personalized precision medicine.

Summary
  • Neutrophils are an important component of several human and mouse tumors.

  • The contribution of tumor-associated neutrophils (TANs) to tumor insurgence and progression may depend on tumor type and stage.

  • Multiple factors present in the tumor microenvironment shape TAN phenotype and function.

  • Neutrophils are present in tumor-bearing hosts as a heterogeneous population.

  • TANs may represent a valuable prognostic marker for patient's clinical outcome and a predictive biomarker for therapy.

Abbreviations

     
  • 5-FU

    5-fluorouracil

  •  
  • Alox5

    5-lipoxygenase

  •  
  • APC

    antigen-presenting cell

  •  
  • CRC

    colorectal cancer

  •  
  • CTLA-4

    cytotoxic T lymphocyte associated protein 4

  •  
  • ER

    endoplasmic reticulum

  •  
  • G-CSFR

    granulocyte colony-stimulating factor receptor

  •  
  • g-MDSCs

    granulocytic myeloid-derived suppressor cells

  •  
  • HER-2

    human epidermal growth factor receptor 2

  •  
  • HGF

    hepatocyte growth factor

  •  
  • HLA-DR

    human leukocyte antigen-D related

  •  
  • ICAM-1

    intercellular adhesion molecule 1

  •  
  • IFN

    interferon

  •  
  • iNOS

    inducible nitric oxide synthase

  •  
  • LDN

    low-density neutrophils

  •  
  • LLC

    lewis lung carcinoma

  •  
  • LOX-1

    lectin-type oxidized LDL receptor 1

  •  
  • LTB4

    leukotriene B4

  •  
  • LXR

    liver X receptor

  •  
  • MDSC

    myeloid-derived suppressor cell

  •  
  • MET

    mesenchymal epithelial transition factor/hepatocyte growth factor receptor

  •  
  • MMTV-PyMT

    mouse mammary tumor virus-polyoma middle tumor-antigen

  •  
  • NET

    neutrophil extracellular trap

  •  
  • NDNs

    normal-density neutrophils

  •  
  • NLR

    neutrophil-to-lymphocyte ratio

  •  
  • NSCLC

    non-small cell lung cancer

  •  
  • PD-1

    programmed cell death 1

  •  
  • RORC1

    RAR-related orphan receptor γ 1

  •  
  • ROS

    reactive oxygen species

  •  
  • SOCS3

    suppressor of cytokine signaling-3

  •  
  • STAT3

    signal transducer and the activator of transcription 3

  •  
  • TAN

    tumor-associated neutrophils

  •  
  • VEGF

    vascular endothelial growth factor

Acknowledgments

The contributions of the European Commission [ERC project PHII-669415], Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) [PRIN 2015YYKPNN] and Associazione Italiana Ricerca sul Cancro [AIRC IG-19014 and AIRC 5x1000-9962 to A.M. and AIRC ID18475 to S.J.] are gratefully acknowledged.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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