Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology

Claudia A Dumitru; Katrin Moses; Sokratis Trellakis; Stephan Lang; Sven Brandau

doi:10.1007/s00262-012-1294-5

. 2012 Jun 13;61(8):1155–1167. doi: 10.1007/s00262-012-1294-5

Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology

Claudia A Dumitru ¹, Katrin Moses ¹, Sokratis Trellakis ¹, Stephan Lang ¹, Sven Brandau ^1,^✉

PMCID: PMC11028504 PMID: 22692756

Abstract

Accumulating evidence indicates that myeloid cells are critically involved in the pathophysiology of human cancers. In contrast to the well-characterized tumor-associated macrophages, the significance of granulocytes in cancer has only recently begun to emerge. A number of studies found increased numbers of neutrophil granulocytes and granulocytic myeloid-derived suppressor cells (GrMDSCs) both in the peripheral blood and in the tumor tissues of patients with different types of cancer. Most importantly, granulocytes have been linked to poor clinical outcome in cancer patients which suggests that these cells might have important tumor-promoting effects. In this review, we will address in detail the following major topics: (1) neutrophils and GrMDSCs in the peripheral blood of cancer patients—phenotype and functional changes; (2) neutrophils and GrMDSCs in the tumor tissue—potential mechanisms of tumor progression and (3) relevance of neutrophils and GrMDSCs for the clinical outcome of cancer patients. Furthermore, we will discuss the advantages and disadvantages of the current strategies used for identification and monitoring of human MDSCs. We propose a six-color immunophenotyping protocol that discriminates between monocytic MDSCs (MoMDSCs), two subsets of GrMDSCs and two subsets of immature myeloid cells in human cancer patients, thus, allowing for an improved characterization and understanding of these multifaceted cells.

Keywords: Neutrophils, MDSC, Tumor progression, Immunophenotyping

Introduction

A vast body of evidence supports the importance of inflammatory cells in the progression of different types of cancer. Among myeloid cells, tumor-associated macrophages (TAMs) are the best characterized tumor promoters (very recently reviewed by Balkwill and Mantovani [1]). In the last decade, however, new myeloid ‘players’ emerged in the field: neutrophils and MDSCs.

Polymorphonuclear neutrophil granulocytes account for approximately 60 % or even up to 70 % of leukocytes in human peripheral blood. The immediate activity of these cells is absolutely essential to protect the human host from detrimental microbial challenge long before adaptive immunity becomes activated. More recently, a role for neutrophils also in chronic inflammatory processes and in cancer-associated inflammation has been emerging. Large clinical studies showed that neutrophil numbers and neutrophil activity in the peripheral blood are altered in cancer patients and those alterations were of clear prognostic relevance in a number of tumor entities [2–4]. In addition, neutrophils release cytokines, chemokines and granule proteins, which shape the tumor tissue microenvironment and, thus, promote tumor progression and metastasis [5, 6].

In recent years and stimulated by studies from murine tumor models, the emergence of the so-called myeloid-derived suppressor cells (MDSCs) added an extra level of complexity to the field. Murine MDSCs were initially described as CD11b/Gr-1-double-positive cells, which were significantly expanded in the tumor, spleen, blood and bone marrow of tumor-bearing animals. Lately, subsets of murine MDSCs have been defined using additional marker antigens. Based on the expression of the Gr-1 antigens Ly-6G and Ly-6C, granulocytic and monocytic murine MDSCs can be identified. According to a current hypothesis, murine MDSCs originate in the bone marrow of tumor-bearing mice, accumulate in the periphery and circulation as the tumor progresses and finally enter the malignant tissue, where they become activated after exposure to local tumor-associated factors [7]. Upon activation, they acquire immunoregulatory, immunosuppressive and tissue-remodeling properties.

While there is accumulating evidence for such a scenario in murine models of cancer, the identity, subset definition, function and pathophysiological relevance of putative MDSC in human oncology is still largely unclear. Some early studies suggested the induction of a heterogeneous mixture of immature and progenitor cells in human cancer patients [8, 9] while other studies suggested activated mature neutrophils as human correlates of murine MDSC [10, 11]. Myeloid regulatory cells (including neutrophils and MDSC) are intensively investigated and debated in human oncology. However, especially with regard to neutrophils and granulocytic MDSC (Gr-MDSC), several major differences exist between most murine studies and the currently growing number of human studies. The following caveats must be carefully considered when proposing direct human correlates for murine MDSC.

Neutrophils represent the majority (roughly two-thirds) of white blood cells in humans. In contrast, neutrophils are by far less frequent in mice (maximum one-third or below).
Compared to humans, the expansion of myeloid cells is more pronounced in certain strains of mice. While Gr-1/CD11b double-positive cells account for only 5–10 % of splenic leukocytes in certain strains of naïve mice, this number rises to more than 30 % in the respective tumor-bearing mice [12].
In mice, CD11b and Gr-1 (subdivided into Ly-6G and Ly-6C) are well-established markers to identify monocytic and granulocytic MDSC. In humans, the Gr-1 antigens are not available, and this dramatically complicates a direct comparison of murine and human MDSCs and MDSC subsets.
In mice, many studies are carried out in transplant tumor models (sometimes even heterotopic and not orthotopic) and models with high tumor load and rapid tumor growth. In humans, tumor growth and progression is a much slower and a chronic process. It can be assumed that these differences will have a profound impact on the modulation and disturbance of myeloproliferation and myelodifferentiation in mice versus humans.
The mechanisms and relative importance of various modes of immunosuppression (e.g., NO, ROS, Arginase) are different between humans and mice.
Finally, the production of immunoregulatory cytokines and other molecules differs between murine and human neutrophils. For example, secretion of IL-10 is well established in murine neutrophils [13], while the vast majority of human studies conclude that neutrophils do not secrete detectable amounts of IL-10 [14–16].

Considering the above-mentioned caveats, this review will focus on the unique features of neutrophils and MDSC in human cancer patients.

Neutrophils and MDSCs in the peripheral blood of cancer patients

Neutrophils

Several studies have reported elevated neutrophil counts in the peripheral blood of patients with different tumor entities such as breast [17], ovarian [18], colon [19], pancreatic [20], nasopharyngeal [21], cervical [22] cancer and melanoma [3]. Neutrophil expansion was independent of infections and associated with poor disease outcome (see below). Recent studies in our group demonstrated an increase in peripheral blood neutrophils and enhanced inflammatory activity in head and neck squamous cell carcinoma (HNSCC) patients [23]. Neutrophils in HNSCC patients showed lower inducible ROS production, reduced spontaneous apoptosis and contained an increased number of immature CD66b⁺CD16^neg neutrophils [24]. These findings were confirmed by Choi et al. [25], who found an increased frequency of CD11b⁺CD15⁺CD16^low granulocytes in the blood of terminal lung, breast and gastrointestinal cancer patients with poor prognosis. A reduced oxidative burst capability of neutrophils has also been reported in the context of acute lymphoblastic leukemia [26] and hepatocellular carcinoma [27]. Reduced chemotactic abilities of neutrophils were found in lung cancer patients [28], and an impaired intracellular killing by neutrophils was described in bladder carcinoma [29]. Neutrophils from patients suffering from squamous cell carcinoma of the oral cavity showed a changed secretion pattern for several immunomodulatory molecules. Specifically, neutrophils displayed an increased IL-1beta and IL-1Ra secretion [30], higher VEGF and lower IL-18 release [31], a reduction in sTRAIL [32] as well as an increase in the secretion of IL-17A and IL-17E [33]. Diverging observations have been made concerning apoptosis of neutrophils in cancer patients. While some studies demonstrated reduced apoptotic features of neutrophils in different HNSCC subtypes [24], others showed accelerated apoptosis rates, changed expression of pro- and anti-apoptotic molecules and an elevated caspase-8 activity in the neutrophils of a oral squamous cell carcinoma patient cohort [34]. Interestingly, CD11b⁺ CD15⁺ neutrophils from melanoma patients were shown by De Santo et al. [35] to secrete the immunosuppressive cytokine IL-10 probably induced by serum amyloid A (SAA). However, secretion of IL-10 is not generally associated with human neutrophils, and instead human monocytes produce high amounts of this cytokine in response to stimulation with SAA [14]. Consequently, these findings have been challenged for melanoma [14] and for HNSCC (own unpublished observation).

MDSCs

MDSCs were described and investigated in different organs (bone marrow, blood, secondary lymphoid organs, tumor tissue) of mice. It is not feasible to obtain this material in sufficient quantity and in a controlled fashion from large numbers of human cancer patients. Consequently, most human studies focus on MDSC obtained from peripheral blood.

Because of the lack of the Gr-1 antigen, together with other differences mentioned above, immunophenotyping of MDSCs differs between human and murine studies. Initial studies on putative myeloid cells with immunoregulatory function observed the presence of granulocytes, which co-purified with mononuclear cells in peripheral blood density gradients from cancer patients. Those CD15⁺ granulocytes exerted T cell suppressive functions and showed an activated phenotype [11]. At the same time, Almand et al. [8] identified a population of immature myeloid cells, Lin^negHLA-DR^neg, inhibiting T cell responses in cancer patients. Today, 10 years later, the full plasticity and complexity of myeloid regulatory cells and subsets thereof has emerged. Major markers involved in the description of MDSC include common myeloid markers such as CD11b and CD33. HLA-DR, often in combination with CD14, is used to identify monocytic MDSC while CD15 serves as a marker for granulocytic MDSCs. Other markers employed for MDSC immunophenotyping include CD66b, CD16, CD83, DC-SIGN, IL4-receptor alpha (IL4Rα), VEGFR and CD34 [36].

Although some very recent studies suggest that peripheral blood MDSCs are of prognostic value in cancer patients, the use of MDSC in clinical oncology is hampered by the fact that no standardized and generally accepted immunophenotyping scheme exists, which allows for a clear discrimination of human MDSC subsets. Nevertheless, most of the recent studies suggest that two major human MDSC subsets exist: monocytic MDSC (MoMDSC) and granulocytic MDSC (GrMDSC). Immunosuppressive MoMDSC express the monocytic marker CD14 but are HLA-DR^neg/low. They were shown to be elevated in the blood of patients suffering from melanoma [37, 38], hepatocellular carcinoma [39], renal cell carcinoma [40], prostate cancer [41], multiple myeloma [42], bladder carcinoma [43] and gastrointestinal cancer [44]. Potential additional markers include CD80, CD83 and DC-SIGN [38]. GrMDSCs were originally defined as granulocytic cells that are enriched in the PBMC fraction after density gradient separation. They commonly express CD15 and CD66b, while further markers vary between different studies. In renal cell carcinoma, described subsets comprise CD14^negCD15⁺ [45], CD11b⁺CD14^negCD15⁺ [46] and CD11b⁺CD33⁺CD66b⁺VEGFR1⁺ CD14^negCD15⁺ [10]. Lung cancer and pancreatic adenocarcinoma patients have elevated levels of CD11b⁺CD33⁺CD15⁺ cells [47, 48] or CD11b⁺CD33⁺CD14^negCD15⁺ cells [49] among PBMC. Further studies showed CD11b⁺CD15⁺ cells in melanoma patients [50] and bladder cancer (CD33^low) [51]. GrMDSC in glioblastoma were described as CD11b⁺CD33⁺HLA-DR^neg CD14^negCD66b⁺CD15⁺ [52, 53]. We could show that GrMDSC in head and neck, urologic and lung cancer patients, are CD33⁺HLA-DR^negCD66b⁺. GrMDSC can be further subdivided into CD16^neg/low and CD16^+/high cells. The former represent long-lived immature GrMDSC with reduced migratory potential toward inflammatory stimuli [54]. The latter display the phenotype of activated granulocytes [10, 11, 50, 53]. It is important to note that both immature granulocytes and activated granulocytes display altered buoyancy in density gradients resulting in similarly altered sedimentation properties. Thus, it appears that both types of GrMDSC, immature and activated, exist in cancer patients which makes functional assays essential for their characterization.

Several studies identified immunosuppressive cells that were negative for mature lineage markers (Lin, HLA-DR) and expressed CD11b together with the common myeloid marker CD33. Interestingly, these cells did not express either monocytic (CD14) or granulocytic (CD15, CD16) markers and therefore cannot be placed in one of the two main categories described above [8, 52, 55–57]. Two of the studies also determined the nuclear morphology of these cells and found that they have predominantly a precursor phenotype [8, 57]. Thus, these cells seem to be immature myeloid cells (ImMC), which may further differentiate to become either MoMDSC or GrMDSC. Finally, MDSCs with a Lin^negHLA-DR^negCD33⁺ phenotype have been described by several other studies. These cells were reported to be negative for CD14 (and, therefore, are no typical MoMDSCs), but further characterization is warranted for conclusive immunophenotyping in these cases [58–62]. The markers that have been used to identify MDSCs in cancer patients thus far are summarized in Table 1. Furthermore, this table contains information regarding the immunosuppressive activities and the nuclear morphology of MDSCs investigated in these studies (Table 1).

Table 1.

Immunophenotyping used for identification of different subtypes of MDSC in human cancers

MDSC subtype	Phenotype	Nuclear morphology	Suppressive activity	Tumor entity	References
GrMDSC	CD15⁺	Poly	Yes	Pancreas, colon and breast cancer	[11]
	CD14^neg CD15⁺	ND	Yes	Renal carcinoma	[45]
	CD11b⁺ CD15⁺	ND	Yes	Uveal melanoma	[50]
	CD11b⁺ CD15⁺ CD33^low	Poly	Yes	Bladder carcinoma	[51]
	CD11b⁺ CD14^neg CD15⁺	Poly	Yes	Renal carcinoma	[46]
	CD11b⁺ CD33⁺ CD15⁺	Poly + mono	Yes	NSCLC	[48]
	CD11b⁺ CD33⁺ CD15⁺	Poly	ND	Pancreatic adenocarcinoma	[47]
	CD11b⁺ CD33⁺ CD14^neg CD15⁺	Poly	Yes	NSCLC	[49]
	CD11b⁺ CD33⁺ CD66b⁺ VEGFRI⁺ CD14^neg CD15⁺	Poly	Yes	Renal carcinoma	[10]
	CD11b⁺ CD33⁺ HLA-DR^neg CD14^neg CD66b⁺ CD15⁺	ND	Yes	Glioblastoma	[52]
	CD11b⁺ CD33⁺ HLA-DR^neg CD14^neg CD66b⁺ CD15⁺	Poly	Yes	Glioblastoma	[53]
	CD33⁺ HLA-DR^neg CD66b⁺	Precursor	Yes	HNSCC, urologic and lung cancer	[54]
	CD33⁺ HLA^neg CD11b⁺ CD15⁺	ND	ND	Gastrointestinal cancer	[44]
MoMDSC	CD14⁺ HLA-DR^neg/low	ND	Yes	Melanoma	[37]
	CD14⁺ HLA-DR^neg/low	ND	Yes	Hepatocellulor carcinoma	[39]
	CD14⁺ HLA-DR^neg/low	ND	ND	Renal carcinoma	[40]
	CD14⁺ HLA-DR^neg/low	ND	Yes	Prostate cancer	[41]
	CD14⁺ HLA-DR^neg/low	ND	ND	Multiple myeloma	[42]
	CD14⁺ HLA-DR^neg/low	ND	Yes	Bladder carcinoma	[43]
	CD14⁺ HLA-DR^neg/low CD33⁺	ND	ND	Gastrointestinal cancer	[44]
	CD14⁺ HLA-DR^neg/low CD80⁺ CD83⁺ DC-SIGN⁺	ND	Yes	Melanoma	[38]
	CD14⁺ IL4Ra⁺	ND	Yes	Melanoma, colon carcinoma	[65]
ImMc (non-MoMDSC non-GrMDSC)	Lin^neg HLA-DR^neg CD14^neg CD15^neg	Precursor	Yes	HNSCC, NSCLC, breast cancer	[8]
	Lin^neg HLA-DR^neg CD33⁺ CD11b⁺ CD14^neg CD16^neg	ND	ND	Glioblastoma	[56]
	Lin^neg HLA-DR^neg CD33⁺ CD11b⁺ CD14^neg CD16^neg	ND	ND	Gastrointestinal cancer (pancreatic)	[55]
	Lin^neg HLA-DR^neg CD33⁺ CD11b⁺ CD14^neg CD16^neg	Precursor	Yes	Colorectal cancer	[57]
	HLA-DR^neg CD33⁺ CD14^neg CD15^neg	ND	Yes	Glioblastoma	[52]
CD14^neg (non-MoMDSC)	Lin^neg HLA-DR^neg CD33⁺ CD14^neg	Mixed	Yes	Metastatic renal cell carcinoma	[61]
	Lin^neg HLA-DR^neg CD33⁺ CD14^neg	ND	ND	Metastatic renal cell carcinoma	[62]
	Lin^neg HLA-DR^neg CD33⁺ CD14^neg	ND	ND	Melanoma	[59]
	Lin^neg HLA-DR^neg CD33⁺ CD11b⁺ CD14^neg	ND	Yes	Breast cancer	[60]
	CD14^neg CD11b⁺ CD33⁺	ND	Peripheral: no Intratumoral: yes	HNSCC	[58]

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If available, information regarding the immunosuppressive activities and nuclear morphology of cell subsets is shown. Please refer to the text for a more detailed description of the cell subsets.

Poly polymorphonuclear, mono mononuclear, ND not determined. Reference numbers are given in square brackets

Neutrophils versus GrMDSCs

Categorizing granulocytes as GrMDSC or neutrophils in cancer patients remains a challenge in the field of tumor immunobiology. To overcome this problem, it is still necessary to determine precisely the molecular and functional differences between these cells. However, such detailed analyses are only available in murine models at present. Very recent studies performed large-scale gene analysis of murine GrMDSC and neutrophils, respectively [63, 64]. In addition, Youn and co-workers determined the morphological and functional differences between the two cell types [64]. Some of the most important findings of these studies are summarized in Table 2. Notably, while GrMDSCs were consistently isolated from the spleens of tumor-bearing mice, neutrophils were isolated either from bone marrow [63] or from spleens and peritoneal cavity of tumor-free mice after casein injection [64]. This might explain the discrepancies found in the read-outs and does not facilitate a direct comparison between the two studies.

Table 2.

Molecular and functional characteristics of GrMDSCs versus neutrophils in mice and humans

	Mice			Humans
	GrMDSC	Neutrophils		GrMDSC	Neutrophils
	Spleen	Bone marrow	Spleen/peritoneal cavity	Blood	Blood
Myeloperoxidase	Low [63] High [64]	High [63]	Low [64]	ND	ND
Arginase	High [64]		Low [64]	High [10]	Low [10]
ROS/oxidative burst	High [63] High [64]	High [63]	Low [64]	Low [62]	High [62]
Migration/chemokines	High [63] Low [64]	Low [63]	High [64]	Low [62]	High [62]
Cytokines	High [63] Low [64]	Low [63]	High [64]	Low [62]	High [62]
TLR signaling	High [63] Low [64]	Low [63]	High [64]	ND	ND
Spontaneous apoptosis	High [63] High [64]	Low [63]	High [64]	Low [62]	High [62]
Nuclear morphology	Poly [64]	ND	Poly [64]	Poly [10] Precursor [62]	Poly [10] Poly [62]

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‘Low’ and ‘High’ indicates relative values when GrMDSCs are directly compared to neutrophils. Poly polymorphonuclear, ND not determined. Reference numbers are given in square brackets

In cancer patients, direct evidence for molecular and functional differences between GrMDSC and neutrophils is limited to only two studies. In renal carcinoma, Rodriguez and co-workers found GrMDSC with significantly increased arginase mRNA and release, respectively, compared to neutrophils from the same patients or from healthy donors [10] (Table 2). In head and neck cancer, we recently identified a subpopulation of GrMDSC with reduced migration, spontaneous apoptosis, LPS-induced IL-8 release and oxidative burst, respectively, compared to autologous mature neutrophils [54] (Table 2). Interestingly, the GrMDSC identified in HNC patients differed from the renal carcinoma GrMDSC in regard to nuclear morphology (Table 2). These findings suggest that at least two subtypes of GrMDSC exist in cancer patients and underline the necessity for detailed characterization of these cells.

Considerations for Immunophenotyping and Immunomonitoring of MDSCs

As described above, a plethora of markers is currently used to identify human MDSCs and human MDSC subsets. We will discuss the most commonly used markers with special respect to their utility for GrMDSC immunophenotyping.

In many studies, the term “lineage negativity, Lin^neg” is used. However, this term is not exactly and consistently defined, because lineage-negativity cocktails from different companies may consist of different marker panels and especially differ in the consideration of CD16. For example, BD Bioscience markets three different cocktails all of which contain CD3, CD14, CD19, CD20, but only two have additional CD56 and just one includes CD16. The cocktail containing the most markers is sold by eBioscience while BioLegend also offers two cocktail sets that differ in the presence of CD16. At the same time, this marker is clearly expressed on GrMDSC [10, 25] and essential to immunophenotype GrMDSC [54] (Fig. 1). Lineage-negativity cocktails containing CD16 may exclude a subset of GrMDSC from further analysis and accidentally define these cells as ImMCs.

Fig. 1 — Proposed immunophenotyping scheme for MDSC discrimination by flow cytometry. PBMC were isolated from fresh blood samples by density gradient centrifugation and stained for the indicated markers. CD33 distinguishes myeloid cells from non-myeloid cells. MoMDSCs are identified by the monocytic marker CD14, high expression of CD33 (CD33⁺) and low expression of HLA-DR (HLA-DR^low). HLA-DR^negCD33^dim cells are divided into CD66b^neg ImMC and CD66b⁺ GrMDSC. CD16 and CD11b are used to differentiate between subsets of GrMDSC, namely immature CD11b^neg and/or CD16^neg and mature activated CD16⁺CD11b⁺ GrMDSC. Please note that, similar to GrMDSC, also CD33^dimHLA-DR^negCD66b^neg cells consist of CD11b⁺ and CD11b^neg cells. Conclusion: CD14, CD66b, CD33 and HLA-DR are required to define MoMDSCs, GrMDSCs and ImMCs, CD11b and CD16 are useful to define further subsets

CD14 and CD15 are generally considered as monocytic and granulocytic markers, respectively, but they are not exclusively expressed on these cells. Neutrophils also express low amounts of CD14, and monocytes can be slightly positive for CD15 which makes the definition of subpopulations even more difficult. Originally identified in murine studies, IL4Rα has also been investigated on human MDSC. Mandruzzato et al. show an upregulation of IL4Rα on Gr- and MoMDSC in colon cancer and melanoma patients. However, expression of IL4Rα on human MDSC subsets is rather weak, which hampers the use of this marker for easy and clear subset definition. Furthermore, there is no clear correlation between IL4Rα expression and the immunosuppressive activity of different MDSC subsets. For instance, Mandruzzato et al. [65] found that expression of IL4Rα correlated with the immunosuppressive activity only in CD14⁺ monocytic cells (and not in GrMDSC), while a later study observed that also immunosuppressive GrMDSC express IL4Rα in NSCLC patients [49].

In many published studies, MDSCs are defined as HLA-DR^neg/lowCD33^dim/+CD11b⁺, sometimes in combination with further lineage markers. While this combination is useful to define overall changes in the myeloid cell compartment of tumor patients, it does not unequivocally and precisely define human MDSC subsets and exclude CD11b^neg myeloid progenitors (see below).

Testing different combinations of markers and gating strategies in melanoma and HNSCC patients, we developed a six-color immunophenotyping strategy to distinguish the three major human MDSC populations (MoMDSC, GrMDSC and ImMC,). Furthermore, our immunophenotyping strategy allows us to distinguish different subsets of GrMDSC. This staining protocol utilizes the most frequently used markers of the current literature (CD33, CD11b, CD14, HLA-DR) and replaces CD15 by a combination of CD66b and CD16 to specifically identify two new GrMDSC subsets [54]. Applying this new immunophenotyping strategy might allow for better identification and quantification of human MDSC subpopulations (Fig. 1).

Neutrophils and MDSCs in the tumor tissue

While there is very little information available about tumor-infiltrating MDSC in human cancer, accumulating evidence indicates an important role of tumor-infiltrating neutrophils in the pathophysiology of cancer. Within the tumor tissue, neutrophils can potentially modulate multiple cellular processes that may ultimately lead to tumor progression. Several studies on murine models indicated that tumor-infiltrating neutrophils promote angiogenesis, particularly via release of MMP9. For instance, Nozawa and co-workers showed that MMP9-expressing neutrophils accumulated in angiogenic dysplasias/tumors and that depletion of neutrophils significantly reduced the initial angiogenic switch [66]. In melanoma and fibrosarcoma-bearing mice, depletion of neutrophils—which strongly expressed VEGF and MMP9—reduced tumor growth [67], while inhibition of neutrophil influx in the tumors by anti- IL-8 neutralizing antibodies reduced angiogenesis in two murine xenograft models [68]. The link between neutrophils and angiogenesis was recently demonstrated in cancer patients when Kuang and co-workers showed that tumor-infiltrating neutrophils are major sources of MMP9 and correlate with angiogenesis progression in hepatocellular carcinoma [6]. A role for neutrophils as major sources of MMP9 has also been observed in HNSCC patients, and we recently showed that tumor-infiltrating neutrophils expressed MMP9 at higher levels than any other cell type within the tumor tissue [69].

Apart from angiogenesis, neutrophils modulate tumor migration and invasion which, consequently, might promote tumor metastasis [70]. It has been shown that neutrophils enhance invasion in various cancer types, such as fibrosarcoma [71], breast carcinoma [72], NSCLC [73] or hepatocellular carcinoma [74]. Here, neutrophils display a highly complex behavior since they can regulate invasion at multiple levels. On the one hand, neutrophils might directly degrade the extracellular matrix (ECM) through release of MMP9. Importantly, neutrophils were shown to release TIMP-free MMP9 [75], which can be rapidly activated thus, facilitating invasion. On another hand, neutrophils might ‘prime’ the tumor cells to degrade the ECM, through activation of tumoral MMP2 via MT1-MMP [71]. Additionally, neutrophils might enhance the motility of tumor cells by phosphorylating FAK (focal adhesion kinase) and paxillin or by activating Rho kinases [76].

It has been suggested that neutrophils promote also the proliferation of tumor cells [77, 78]. These findings seem, however, rather contradictory to the role of neutrophils in tumoral migration/invasion, since migrating/invasive cells often display reduced proliferation [79, 80]. In fact, recent studies from our group showed that neutrophils enhance the migration, but not the proliferation of HNSCC cells [81], and we found that neutrophils even reduce HNSCC cells proliferation at later times (own unpublished observations). Thus, the exact role of neutrophils in the proliferation of tumor cells remains unclear and needs to be addressed in future studies.

Finally, neutrophils might contribute to immune suppression and, subsequently, tumor progression in a manner similar to that of MDSCs. Although mainly systemic (in peripheral blood), the immunosuppressive effects of neutrophils and MDSCs might also occur directly in the tumor tissue. Corzo and co-workers isolated CD11b⁺/CD33⁺/CD14^neg cells from HNSCC tissues which displayed inhibitory effects on T cells proliferation ex vivo [58]. Recently, Rotondo and colleagues showed that neutrophils stimulated with NSCLC supernatants release immunosuppressive arginase I pre-stored in their granules. Furthermore, the authors demonstrated that neutrophils infiltrating the NSCLC tissues displayed reduced intracellular levels of arginase I [82]. It would be, therefore, tempting to speculate that tumor-infiltrating neutrophils might release arginase I in the tumor microenvironment to promote local immune suppression.

The neutrophil-tumor interactions at molecular level have been only scarcely addressed thus far. Several studies showed that tumor cells activate neutrophils which, in turn, modulate tumor biology and functions. At each step of this equation, direct cell–cell contact and/or release of soluble factors have been proposed as potential mechanisms. For instance, in breast carcinoma, neutrophils clustered tumoral ICAM-1 and promoted migration [76] or released Oncostatin M and promoted invasion of the tumor cells [72]. In hepatocellular carcinoma, neutrophils were activated by tumor-derived hyaluronan via TLR4 and promoted tumor cell motility [83]. We have recently shown that HNSCC-derived MIF stimulates neutrophils to release (yet unidentified) soluble factors that enhance the migratory properties of the tumor cells in a feed-back manner [81]. Other potential players mediating the interactions between neutrophils and tumor cells include neutrophil-derived HGF [74, 84], neutrophil elastase/cathepsin G/proteinase-3 [5, 71] or tumoral sLeX (Sialyl Lewis X) upregulation by neutrophil-derived TNFa [73]. Taken together, these findings indicate that the molecular interactions between neutrophils and tumor cells are very complex and that extensive characterization of these mechanisms is still required.

Neutrophils and MDSCs in cancer patients—clinical relevance

Neutrophils

An association between high blood neutrophil counts and poor clinical outcome has been already described in early studies. Shoenfeld and co-workers observed that in patients with several non-hematological malignancies, in particular lung and colorectal carcinoma, high leukocytosis significantly associated with shorter survival and presence of metastasis. Further analysis of the white blood cell subtypes indicated that an increase in the mature polymorphonuclear cells was mainly responsible for the leukocytosis observed in these patients [85]. Since then, many studies suggested that high neutrophil counts (mainly indicated by high neutrophil to lymphocyte ratios (NLR)) associate with poor clinical outcome in different types of cancer. In this review, we will list and address some of the most recent studies, which have been published in the last 5 years.

In patients undergoing liver resections for colorectal liver metastasis (440 patients), elevated NLR was the sole positive predictor of recurrence on univariate analysis [86]. The same group found that high NLR associated with tumor recurrence and poor survival in hepatocellular carcinoma patients undergoing orthotopic liver transplantation [87]. Similarly, in another cohort of hepatocellular carcinoma patients, high pre-operative NLR was found to be an adverse predictor of disease-free and overall survival [88]. Cho and co-workers showed that patients with epithelial ovarian cancer have significantly higher preoperative NLR than patients with benign ovarian cancer, benign gynecologic diseases or healthy controls. Furthermore, the authors found that high NLR was the most powerful predictive variable for poor prognosis using Cox multivariate analysis [18]. Teramukai and co-workers showed that elevated neutrophil counts associated with short overall and progression-free survival in patients with advanced NSCLC, while no such associations were found regarding lymphocyte or monocyte counts [4]. In a large collective of gastric cancer patients that underwent gastrectomy (1,028 patients), elevated NLR was found to be an independent risk factor for reduced survival [89]. Ohno and co-workers investigated the impact of high NLR in 192 patients with nonmetastatic renal cell carcinoma who underwent nephrectomy and found that increased pretreatment NLR was an independent predictor of recurrence in multivariate analysis [90]. Finally, very recent studies found an association between elevated NLR and worse disease-free and overall survival in esophageal carcinoma patients [91], while An and co-workers showed that high NLR is an independent prognostic factor for poor survival and might additionally predict the response to chemotherapy in nasopharyngeal carcinoma patients [21]. Taken together, these findings indicate an association of high blood neutrophil counts with poor clinical outcome in cancer patients. However, it has to be mentioned that the cutoff values for NLR differed greatly between studies. While several studies considered NLR ≥ 5 as ‘high’, other studies defined high NLR as ≥ 3.7 [21] or even ≥ 2.7 [90]. Furthermore, the NLR cutoff values were often chosen empirically. It would be, therefore, relevant for future studies to optimize the NLR cutoff values for each type of cancer (i.e., ROC curve analysis) and, thus, strengthen the validity of these data.

The clinical relevance of tumor-infiltrating neutrophils has only recently begun to emerge. Direct associations between tumor-infiltrating neutrophils and poor clinical outcome of patients have been described for several types of cancer. Notably, most of the studies reporting these findings have been published in the last 3 years, which emphasizes the increasing importance and relevance of neutrophils in cancer biology. In metastatic renal carcinoma, the presence of intratumoral neutrophils has been linked to poor survival in patients receiving IL-2 immunotherapy [2]. A more recent study from the same group reported a negative impact of neutrophils in localized clear cell renal carcinoma and showed that the presence of intratumoral neutrophils significantly associates with higher tumor size and short recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS), respectively [92]. Two recent back-to-back studies investigated the impact of tumor-infiltrating neutrophils in hepatocellular carcinoma. In one of these studies, Kuang and co-workers showed that high peritumoral neutrophil numbers are a strong predictor for poor survival in a cohort of 238 patients [6]. The second study demonstrated that intratumoral neutrophils are a poor prognostic factor for hepatocellular carcinoma following resection and showed that neutrophils significantly associate with advanced stage (Barcelona-Clinic Liver Cancer staging), early recurrence and short RFS/OS in 197 patients [93]. A large study on 632 patients with non-small-cell lung carcinoma (NSCLC) showed that high intratumoral neutrophil numbers significantly associate with high cumulative incidence of relapse (CIR) and trend to associate with worse OS [94]. In patients with melanoma stage I/II, the presence of tumor-infiltrating neutrophils was significantly associated with poor survival in 186 patients [95]. Our studies on 99 patients with head and neck squamous cell carcinoma (HNSCC) demonstrated that high neutrophilic infiltration of the tumor tissue associates with high tumor (T) stage and poor survival in patients with advanced disease [23]. Surprisingly, neutrophilic infiltration has been observed even in somewhat ‘immune-privileged’ tissues, such as brain, and one study showed that glioblastoma multiforme (the most aggressive type of brain cancer) exhibits significantly higher numbers of tumor-infiltrating neutrophils compared to more ‘benign’ types of glioma [96].

Several other studies have linked neutrophils with poor outcome of cancer patients, albeit in an indirect manner. For instance, Schwaller and co-workers found that high expression of APRIL (A Proliferation-Inducing Ligand) in tumor lesions correlates with poor survival in patients with diffuse large B cell lymphoma (DLBCL). Interestingly, this study also showed that the main cellular sources of APRIL in these tumors were the infiltrating neutrophils [97]. In another recent study, we demonstrated that high numbers of infiltrating neutrophils correlated with strong macrophage migration inhibitory factor (MIF) expression in HNSCC tumors. Further analysis on a cohort of 91 HNSCC patients revealed a significant association of high tumoral MIF levels with higher N-stage (lymph node metastasis) and poor survival in these patients [81].

MDSCs

In contrast to neutrophils, the role of MDSCs in cancer patients is much less characterized. Although increased numbers of MDSC have been often found in the peripheral blood of cancer patients (see above), only few studies were able to statistically analyze the numbers of MDSCs in relation to clinical parameters. In one of these studies, Diaz-Montero and co-workers found that patients with various solid tumors exhibited significantly higher numbers of circulating HLADR⁻ CD33⁺CD11b⁺ cells compared to healthy volunteers. Furthermore, the numbers of circulating MDSCs were highest in patients with advanced disease (stage IV) and with extensive metastatic tumor burden [60]. In patients with gastrointestinal malignancies, high numbers of HLADR⁻CD33⁺CD15⁻ cells associated with reduced overall survival in multivariate Cox proportional hazard models [44]. Finally, a third study also on patients with gastrointestinal cancer (pancreatic, esophageal and gastric) found that elevated levels of HLADR⁻CD33⁺CD11b⁺ cells were an independent prognostic factor for poor survival [55].

Even less is known about the role of tumor-infiltrating MDSCs in cancer patients. Thus far, only three studies reported parallel analysis of peripheral blood MDSC and of tumor-infiltrating myeloid cells from human tissue. From bladder carcinoma tissue, Eruslanov and co-workers isolated myeloid cells with a CD11b⁺CD15b⁺ phenotype [51]. Porembka and co-workers isolated CD11b⁺/CD15⁺/CD33⁺ cells from tumors of patients with pancreatic adenocarcinoma [47]. Corzo and colleagues identified a subpopulation of CD11b⁺CD14^negCD33⁺ cells in the tumor tissues of HNSCC patients [58]. This study also tested the isolated CD11b⁺CD14^negCD33⁺ cells at functional level and showed that they have high iNOS expression and suppress T cell proliferation, as customary for MDSCs. While these experiments certainly reveal some interesting information on the properties of tumor-infiltrating myeloid cells in HNSCC and other types of cancer, the combination of markers used to characterize these potential MDSCs cannot distinguish putative GrMDSC from conventional tumor-infiltrating granulocytes, which have been shown to influence disease outcome in this and other tumor entities [23].

As no unique markers exist, laborious procedures are required for MDSC identification (i.e., tissue dissociation, simultaneous analysis of multiple markers, functional assays). In addition, nuclear staining of tumor-infiltrating myeloid cells should be performed, which would allow for distinction of polymorphonuclear cells [69] from both mononuclear and immature myeloid cells. Thus, these studies are limited to a very small number of patients, without possibility of statistical analysis, making tumor-infiltrating “bona fide” MDSCs elusive players in the pathophysiology of human cancers. For clinical correlations on large cohorts of patients, it would be necessary to identify a specific marker for these cells and/or perform very complex immunostaining procedures and analysis. Until then, distinguishing tumor-infiltrating putative GrMDSC from tumor-infiltrating neutrophils will remain a great challenge. Therefore, if intratumoral, these cells should currently be referred to as tumor-associated neutrophils (TANs) analogous to the well-known tumor-associated macrophages.

Acknowledgments

We thank Kirsten Bruderek (Department of Otorhinolaryngology, University of Duisburg-Essen) for excellent technical support with the immunophenotyping of MDSC from cancer patients.

Conflict of interest

The authors declare no conflict of interest.

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PERMALINK

Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology

Claudia A Dumitru

Katrin Moses

Sokratis Trellakis

Stephan Lang

Sven Brandau

Abstract

Introduction

Neutrophils and MDSCs in the peripheral blood of cancer patients

Neutrophils

MDSCs

Table 1.

Neutrophils versus GrMDSCs

Table 2.

Considerations for Immunophenotyping and Immunomonitoring of MDSCs

Fig. 1.

Neutrophils and MDSCs in the tumor tissue

Neutrophils and MDSCs in cancer patients—clinical relevance

Neutrophils

MDSCs

Acknowledgments

Conflict of interest

References

ACTIONS

PERMALINK

RESOURCES

Cite

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PERMALINK

Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology

Claudia A Dumitru

Katrin Moses

Sokratis Trellakis

Stephan Lang

Sven Brandau

Abstract

Introduction

Neutrophils and MDSCs in the peripheral blood of cancer patients

Neutrophils

MDSCs

Table 1.

Neutrophils versus GrMDSCs

Table 2.

Considerations for Immunophenotyping and Immunomonitoring of MDSCs

Fig. 1.

Neutrophils and MDSCs in the tumor tissue

Neutrophils and MDSCs in cancer patients—clinical relevance

Neutrophils

MDSCs

Acknowledgments

Conflict of interest

References

ACTIONS

PERMALINK

RESOURCES

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