Cancer Microenvironment (2012) 5:133–149

DOI 10.1007/s12307-011-0091-6

REVIEW PAPER

Origin and Functions of Tumor-Associated Myeloid
Cells (TAMCs)
Antonio Sica & Chiara Porta & Sara Morlacchi &
Stefania Banfi & Laura Strauss & Monica Rimoldi &
Maria Grazia Totaro & Elena Riboldi

Received: 31 May 2011 / Accepted: 13 September 2011 / Published online: 24 September 2011
# Springer Science+Business Media B.V. 2011

Abstract The construction of an inflammatory microenvi- progression and the molecular mechanisms that regulate
ronment provides the fuel for cancer development and such event.
progression. Hence, solid tumors promote the expansion
and the recruitment of leukocyte populations, among which Keywords Tumor-associated myeloid cells (TAMCs) .
tumor-associated myeloid cells (TAMCs) represent a Polarized inflammation . Tumor-associated macrophages
paradigm for cancer-promoting inflammation. TAMCs (TAMs) . Myeloid-derived suppressor cells (MDSCs) .
group heterogeneous phagocytic populations stemming Angiogenic monocytes Tie2+ (TEMs) . Tumor-associated
from a common myeloid progenitor (CMP), that orchestrate neutrophils (TANs)
various aspects of cancer, including: diversion and skewing
of adaptive responses; immunosuppression; cell growth;
angiogenesis; matrix deposition and remodelling; construc- Introduction
tion of a metastatic niche and actual metastasis. Several
evidence indicate that TAMCs show plasticity and/or The cellular content of solid tumors comprises cancer cells
functional heterogeneity, suggesting that tumour-derived and a heterogeneous group of cell populations, including
factors promote their functional “reprogramming” towards fibroblasts, endothelial cells, pericytes and leukocytes.
protumoral activities. While recent studies have attempted Among leukocytes, myeloid cell populations represent a
to address the role of microenvironment signals, the prominent component, both in terms of number and
interplay between cancer cells, innate and adaptive immu- functions, supporting tumor growth and progression [1].
nity is now emerging as a crucial step of the TAMCs Being part of the first line of immune defence mechanisms
reprogramming. Here we discuss the evidence for the (innate immunity), the protumoral role of tumor-associated
differentiation of TAMCs during the course of tumor myeloid cells (TAMCs) appears a paradox of immunity,
which finds its basis on the functional “plasticity” of
myeloid cells, defined as the capability to express different
functional programs in response to different signals (eg.
A. Sica (*) : C. Porta : E. Riboldi
cytokines, growth factors) [1] and/or microenvironment
DiSCAFF, University of Piemonte Orientale A. Avogadro,
via Bovio 6, conditions (eg. acidosis, high interstitial pressure, low
28100 Novara, Italy glucose levels) [2]. Consequently, new attention is directed
e-mail: antonio.sica@pharm.unipmn.it towards mechanisms and molecules driving the protumoral
skewing of TAMCs.
A. Sica
e-mail: antonio.sica@humanitasresearch.it TAMCs include at least four different myeloid popula-
tions (Fig. 1): 1) tumor-associated macrophages (TAMs),
A. Sica : S. Morlacchi : S. Banfi : L. Strauss : M. Rimoldi : considered crucial orchestrators of cancer-related inflam-
M. G. Totaro
mation [3], promoting angiogenesis, immunosuppression,
Istituto Clinico Humanitas, IRCCS,
via Manzoni, 56, tissue remodelling and metastasis [4]; 2) the angiogenic
20089 Rozzano, Milan, Italy monocytes expressing the tunica internal endothelial kinase

4) tumor-associated neutrophils (TANs) that. C5a) into the tumor microen- differentiation to their own advantage. TAMs are recruited into the tumor vironment. TANs participate in tumor promotion by the expression of crucial pro- cytic and monocytic myeloid-suppressor cells (G-MDSC and M. Lin-/Sca1-/c-Kit±/IL-7Rα-/c-mpl±/FcγRlow/CD34±/ Dendritic cells (DCs) belong to the family of myeloid cells . neutrophils (CD11b+/Ly6G+) [9]. In prominent phagocytes population orchestrating cancer-related inflamma- the bone marrow hematopoietic stem cell (HSC) differentiate into tion. the angiopoietin receptor. 9]. promote population of myeloid cells (G-MDSC and M-MDSC) accumulate in the recruitment of circulating cells into both the tumor mass or secondary blood and lymphoid organs. which can tumor angiogenesis [5].134 A. monocytes (CD11b +/Gr1 +/F4/80+/CCR2+)./c-mpl±/ called myeloid-derived suppressor cells (MDSCs) for their FcγRhigh/CD34±/SCL±/GATA-2-/NF-E2-/GATA-1-/GATA- ability to suppress T cells functions. such as Ang2 and differentiate into granulocyte/macrophage progenitors (GMPs). 1 Mechanisms of differentiation and accumulation of TAMCs. despite (CD11b+/Ly6G+) and a monocytic (CD11b+/Ly6C+) sub- their short half-life. Tumors secrete factors TAMCs originate in the bone marrow where hematopoi. GMPs CXCL12. (CMPs. promote the recruitment of etic stem cells (HSCs. S-100. CXCL8). angiogenic factors. TEMs derive from circulating Tie2+ monocytes and are recruited in common myeloid progenitors (CMPs). Tie2-expressing monocytes (CD11b+/Gr1low/-/Tie2+) and angiogenic factors [7]. MDSCs may be recruited by selected lymphoid organs (lymph nodes and spleen) and orientate their functional chemoattractants (CCL2. which sustain myelopoiesis. which can subsequently tumors by hypoxia-inducible chemoattractants. CSF-1) and represent the immunity 2 (Tie2). have been recently proven to participate population. but may also be recruited to the tumor site (MDSCs) that can be further subdivided in a granulocytic [6]. VEGF. and granulo.g. Tumor-associated neutrophils (TANs) stem from circulating give rise to different subsets of circulating cells: monocytes (Mo). Tie2-expressing monocytes (TEM). Fig. During tumour progression an heterogeneous MDSC).c/Kit±/Sca1±/CD34-/CD48-/ circulating cells into the tumor mass. GMPs give rise to different subsets mainly in blood and lymphoid organs during tumor of circulating cells: myeloid-derived suppressor cells progression. which accumulate 3-/EpoR-/C/EBPα±) [8]. neutrophils (PMN). where they contribute to suppression of the adaptive site by chemotactic factors (eg. Lin. and orientate their CD150-) differentiate into common myeloid progenitors functional differentiation to their own advantage [6. Tumors secrete factors which sustain myelopoiesis. in tumor promotion by the expression of crucial pro. Sica et al. 3) the Ly6G and Ly6C subsets of subsequently differentiate into granulocyte/macrophage an heterogeneous population of immature myeloid cells. CCL2. playing a key role in SCL±/GATA-2±/NF-E2±/GATA-1±/GATA-3-). progenitors (GMPs. Lin-/Sca1-/c-Kit ±/IL-7Rα. neutrophils and are recruited in tumors by chemokines (e.

6].g. gliomas.g. CCL5. CCL4. M1. vascular endothelial growth factor. receptor. obesity) in which the evolution providing evidence for an autocrine loop that promotes of activating signals is paralleled by changes in the MDSC recruitment [29. while others (eg. some factors which are found in the tumour microenviron- where myeloid cell plasticity plays as a double-edged ment. conditions (sepsis. melanomas. cancer. classically involved in the recruitment of Toll-like receptor ligands) triggers polarization of “M1” monocytes to inflammatory sites. C-C and C-X-C chemokines (e. TGFβ) and Th2-associated (IL-33. the C5a complement discussed elsewhere [11. cytokines. such as immunosuppressive tion in different types of tumor. Tumor. are crucial sword [1. are specifically associated with certain types of cancer. it became clear that the M1 vs M2 dual subsets in tumors by hypoxia-inducible chemotactic factors such as simplification offers a mechanistic model of the functional the CXCR4 ligand CXCL12 and Angiopoietin-2 (Ang-2) polarization of macrophages. molecules. vaso-active intes- prostate and gastric cancer respectively [20. circulating Tie2-expressing monocytes which are recruited Hence. a prototypic chemo- fibroblasts. in close anthracis). activation [35]. immune complexes in combination with either proximity to nascent tumor vessels. They derive from lipopolysaccharide (LPS) or IL-1β [13. urokinase plasminogen activator (uPa) genesis. resulting in “smouldering” inflammation different tumor cells promotes neutrophils migration both mainly oriented to tune the adaptive immune response and directly and indirectly. TGFβ produced by other functions. Recent studies Neutrophils may be recruited by chemotactic factors have proved that the cross-talk between the different secreted by tumor cells. BD-3) orienting properties have been identified. BD-3) (IL-10. 23]. Sinha and co-workers demonstrated phagocytes is emphasized by different pathophysiological that MDSCs can produce S-100 proteins by themselves. carcinoma cells produce CXCL8. Many other different (e. FGF. chemokines and transcription factors [6]. bacterial products (oedema toxin from Bacillus mainly clustered in hypoxic areas of solid tumors. cancer of the Whereas macrophage exposure to inflammatory cytokines breast. innate and adaptive immune cells) shapes each attractant for neutrophils [31]. CSF-1. such as pro-inflammatory S-100 proteins. IFNγ) and bacterial moieties (e. TGFβ. has been shown to play a role in MDSC recruitment The functional skewing of myeloid populations is an and activation in a cervix cancer model [28]. Within this [20]. bronchoalveolar cellular components of the tumor mass (e.Role of Tumour-Associated Myeloid Cells (TAMCs) 135 stemming from CMPs. Cells with dendritic cell character. it has become evident that immuno- tumor-derived chemotactic factor (TDCF) identified [14] modulatory signals such as IL-4 are more than simple and is currently recognized as the major chemoattractant for inhibitors of macrophage activation. angio- CXCL12) [17–19]. scenario. CCL3. growth factors (e. TAMCs Functions Mechanisms of TAMCs Recruitment Tumour Associated Macrophages (TAMs) Although macro- phages were classically described as powerful inflammatory Chemokine (C-C motif) ligand 2 (CCL2) was the first and cytotoxic cells. polarized activation of macrophages [13]. It has associated DCs (TADCs) generally show an immature been demonstrated that among chemokine receptors. by regulating the expression of to promote angiogenesis and tissue remodelling [1]. such as sarcomas. M2-polarized macrophages tune inflammation. 12] and are not included in the component.g. 33. whereas the tissue micro- [5.and M2-polarizations have been proposed as transforming growth factor-β. growth factors (colony stimulating factors. 30]. uPa. interferon-gamma. new efforts are needed to identify key regulators of myeloid cell plasticity during cancer development. scenario. fibroblast growth the extremes of a continuum of different states of polarized factor. tumor cells. these include properties. in a variety of human tumors “alternative” or “M2” program of activation [33–35]. More recently. but actually induce an monocytes at the tumor site. In addition to IL-4 several signals with M2- 21. tissue remodelling and repair [35]. Further. VEGF) [6. 22] and antimicrobial peptides (β-defensin-3. The extreme versatility of mononuclear for MDSC recruitment. hormones (glucocorticoids. tinal peptide). have also been involved macrophages with anti-microbial and tissue destructive in monocyte migration to neoplastic tissues. 16]. These include [23]. promote resistance against extracellular pathogens.g. CCR2 phenotype and are poor inducers of effective responses to plays a pivotal role in the recruitment and turnover of MDSC tumor antigens. The properties of these cells have been to the tumour site [27]. Tie2-expressing monocytes/macrophages (TEMs) are CSFs). Many of these molecules correlate with TAM infiltra. different classes of molecules. In this adhesion molecules in the endothelium [32]. which interacts with a G protein-coupled present review. environments are likely to elicit simultaneous activation of . colony-stimulating factor-1. IL-21) cytokines . cervix and ovary [15. 24–26]. MDSC recruitment and expansion are regulated by several istics are present in neoplastic tissues [10].g. emerging paradigm of tumor-mediated immunosuppression. Moreover. As an example. melanocortin. 36].

mediators (e. different signalling pathways with opposite influence on hepatocellular and pancreatic carcinomas and in Hodg- macrophage functions. angio- macrophage phenotypes during the course of several genesis and tumor growth [71]. characterized by impaired expression of LPS- . but rather display a reported to induce M2-like polarization [[54. an [75]. Clinical studies suggest that the type of immunity foster cancer development by activating Fcγ immunological profile expressed at the tumor site repre. 69–72] (Figure 2). display infiltrate the precancerous tissues. However. upon human cytomegalovirus cell activation and inducing an M2-like phenotype of TAMs (HCMV) infection. 10. it was suggested that increased growth of transplanted tumors [58]. Sica et al. Many studies have shed light on the intricate signalling lapping functions with the original IFNγ (M1) and IL-4 network that drives myeloid cells towards M2-polarized (M2) induced phenotypes. high production of M1 inflammatory [70]. Erez and colleagues demonstrated that profile. prostaglandin E2 (PGE2). inhibit T-cell activation and enhanced cytokines and/or antibodies may drive the cancer- tumor growth when inoculated in solid tumors [59]. TNF. 52–55]. as B cells do not macrophage drift towards M2 polarization. with upregulation of several M1 and M2 gene CAFs express a distinct inflammatory gene signature transcripts [48]. Similarly. Furthermore. Cancer associated fibroblasts (CAFs) have recently PI3K signalling pathways [46] drives monocytes toward emerged as new players in cancer-related inflammation an atypical M1/M2 reprogramming [47]. Using the K14-HPV16 mouse model of squamous adipose tissue macrophages from obese mice have a mixed carcinogenesis. This hypothesis has recently contrast. changes occurring in its microenvironment. The acquisition of pro-tumoral M2 functions by microenvironment milieu induce heterogeneous signalling TAM is driven by various cytokines and signals expressed events. which exhibit a spontaneous squamous carcinogenesis [74]. in a model of mammary carcinoma. lymphocytes expressing the M2-polarizing cytokines IL-4 tumor growth and malignancy [1. display increased tumor carcinogenesis. tumor angiogenesis and cancer cell proliferation. For example. As an response-specific functional patterns. associated with promotion of TAM recruitment. different macrophage phe. DeNardo et al. represent distinct example. but not B2 established type-2 “suppressive” immunological profile cells. progression of functional changes in response to the Recent studies suggest that different circuits and cells. Recently. Indeed. participate in thesis that macrophages displaying unique tissue-specific or shaping TAM activities [13. In semaphorin 4D (Sema4D) [56] and growth arrest-specific 6 turn. Among these. type 2 vs type 1 shift of tumor-associated inflammation In early phases. markedly inhibited recruitment of TAMs. in vivo ablation of CAFs by a DNA vaccination reported [49–51]. utilizing the MMTV-PyMT model of mammary like phenotypes with immunosuppressive. phenotype. Further. which show an M2. a shift in monocyte. 6. pro-angiogenic carcinogenesis. the interplay between innate and adaptive species. demonstrated that CD4+ T and tissue remodelling activities promotes immune escape. A recent report suggests that B1 cells. contributing to the extensive heterogeneity in within the tumor microenvironment [54]. In particular. MDSCs were lineages [42. IL-6. The role of B cells in shaping the TAM phenotype was Src homology 2-containing inositol-5′-phosphatase-1 originally demonstrated in a K14-HPV16 mouse model of (SHIP1)-deficient mice.136 A. ROS) appears to support neoplastic transformation immunity is emerging as a crucial step in this event [72]. Using the same mouse model of squamous macrophage polarization [60]. 45]. orchestrated remotely. [6]. whereas in established cancers the expression of M2. challenges the including innate immune cells and fibroblasts. 65–68]. cancer and obesity has been model. polarize peritoneal macrophages to an M2-like correlates with poor prognosis. tumor necrosis factor. The view that macrophage activation does not result in the migration-stimulating factor (MSF) and CSF-1 were expression of a single set of functions.(NF-κB) deficient mice. New evidence indicate that polarized inflammation plays MDSCs and regulatory T cells (Tregs). which are respectively involved in promoting mammary epithelial cells. the activation of both NF-κB and [69]. p50 Nuclear factor-κB. Recent and IL-13 potentiate mammary adenocarcinoma metastasis addition to the molecular repertoire of TAMs includes by modulating the pro-tumor properties of TAMs [73]. CD11c± [71]. reactive oxygen Further. thus promoting a a central role during different stages of tumor development. gene expression profiling shown to contribute to tumor progression by suppressing T- studies highlighted that. found a confirmation by the study of Andreu and co- which showed a defective capacity to mount an M2 workers. suggesting that lymphocyte-derived biased phenotype. receptors (FcγR) on resident and recruited myeloid cells sents an independent prognostic factor. as shown in colorectal. CCL2.g. Of note. IL- patterns of gene expression seen in macrophages [37–44]. indicating that differences in activation. In promoting inflammation [3]. strategy. TAMs enhance the invasive potential of malignant (Gas6) [57]. TGF-β. kin’s lymphoma [61–64] notypes have been described with only partially over. In a murine breast cancer diseases such as sepsis. they showed that B cells and humoral resistance [54]. infiltration and functions of innate immune cells must be Notch signalling deficient macrophages.

25. In agreement. under the “remote control” of cancer- associated fibroblasts (CAFs). such as Ang-2 and CXCL12 [24–26. the latter event mainly MDSCs possess several mechanisms for immune suppres- regulated by hypoxia. 3) post-translational modifications of . Further. Hypoxic ECs up-regulate Ang-2 that enhances sion: 1) depletion of arginine.g. CCL5. Differentiation of MDSCs is modulated by characteristics are an immature state and the ability to several tumor-derived factors. which can be co-opted by tumors [75]. IL-6. It was also recently demonstrat- ed that Ang-2 levels in 4T1 mammary tumors correlates with both TEM-derived IL-10 and Treg infiltration. with higher expression of M2 genes. scavenger receptors (CD163. 2 Pathways of polarized activation of tumor associated myeloid TNFα) in TEMs exposed to hypoxia [24]. demonstrating their importance in tumour angiogenesis and tactic factors. These results suggested that Tie2+ monocytes could be a distinct lineage of myeloid cells. tumor microenvironmental signals can convert MDSCs in endothelial cells (ECs) or in TAMs. TAMCs reciprocally influence their protumoral differentiation. Mrc1. In line. 77]. pathways (Figure 2). CCL3. sub-cutaneous tumors growing in Ang-2- overexpressing mice showed increased number of TEMs associated with enhanced microvessels density [81].Role of Tumour-Associated Myeloid Cells (TAMCs) 137 induced pro-inflammatory genes (e. PTGS2/COX2. 25. stabilin-1) and lower levels of pro- inflammatory molecules (IL-1β. committed to execute physiologic pro-angiogenic and tissue-remodeling programs. In addition. Macrophage scaven- ger receptor 2. WNT5A) and are powerful inducers of endothelial cells activation [81]. PGE2. In contrast. COX2. CXCL10. Strikingly. Matrix metallopeptidase 9. human Tie2+ circulating mono- cytes express high levels of pro-angiogenic genes (e. 79]. Despite representing only a small fraction of TAMs (Tie2- tumor-associated macrophages). TNFα. 25. cells (TAMCs). including GM-CSF. inducible nitric oxide synthase. including arginase 1 (Arg1). 76]. pro-angiogenic activity [24. TNF.g. CXCL11) [80]. activation of pro-angiogenic and M2-skewed TEMs 2) production of ROS. mediated by Arg1 and iNOS. CXCL12-CXCR4 axis is a well known circuit driving 1β) with up-regulation of the anti-inflammatory gene IL-10 accumulation of TAMs in hypoxic areas of solid tumors [72. both ablation and adoptive Tie2-expressing Monocytes/Macrophages (TEMs) TEMs transfer studies have demonstrated that TEMs are crucial are a small subset of myeloid cells characterized by the promoters of tumor angiogenesis [5. IL-12. prostaglandin endoperox- ide synthase 2/cyclooxygenase 2. adoptive transfer studies demonstrated that subcutaneous co-injection of tumor cells with TEMs increases tumor vascularization [5]. VEGF and suppress T-cell responses both in vitro and in vivo [82. IL. produce TGFβ that induces the alternative resent an heterogenous population of cells whose common (N2) activation of TANs. 83]. As depicted. 78] The growth [5. wingless-related MMTV integration site 5A. result- ing in suppression of T cells proliferation [78]. but express a more pronounced M2- skewed gene signature. Ang-2 inhibited the expression of M1 cytokines (IL-12 and Fig. They derive from Ganciclovir-driven ablation of Tie2+ monocytes induced a circulating Tie2-expressing monocytes which are recruited significant reduction of both tumour mass and vasculature. T and B lymphocytes. gene expression analysis highlighted that TEMs are highly related to TAMs. 79]. in tumors by hypoxia-induced endothelial-derived chemo. TAMs in concert Myeloid-Derived Suppressor Cells (MDSCs) MDSCs rep- with Tregs and tumor cells. Mannose receptor 1. Msr2. [18]. VEGF-A. MMP9. Tie2 engagement by Ang-2 in both mouse and human TEMs not only elicits a chemotactic response but also enhances their pro-tumoral activities [81]. In two models expression of the angiopoietin receptor Tie2 and powerful of mammary tumours and orthotopic human gliomas. it has been demonstrated that pharmaco- The observations identify the M2-like phenotype of logical inhibition of CXCR4 is associated with a significant TAM as a point of convergence of various pro-tumoral reduction of TEM recruitment into mammary tumors [26]. Noteworthy. iNOS.

are present in physiological conditions. (CD14± CD11b± HLA-DRlow/-) [99. Several factors produced by tumors have been implicated 4) depletion of cysteine. 5) production of TGFβ. CD80. advanced non-small cell lung and PIR-B-deficient M-MDSCs expressed high levels of cancer (CD14. VEGF and PGE2 [82. MDSCs isolated morphology have been described [95. however accumu- of human MDSCs deeply suffers from the lack of specific lating evidence show that MDSCs have characteristics of markers. including granulocyte induction of Tregs [84–91]. Beside their immunosuppressive activities. in the bone marrow. MDSCs MDSCs are CD11b+ Ly6G+ Ly6Clow with granulocyte-like from an IL-1β-enriched tumor microenvironment produce morphology [83]. T cell receptor (TCR) mediated by peroxynitrite generation. between MDSC and T cell [82]. these cells should not be named MDSCs [92]. The cross-talk between MDSCs and MDSCs (G-MDSCs). complement system appears a key regulator of MDSC functions. Other markers of MDSC subsets are: IL-4Rα (CD124). Circulating MDSCs can but they are devoid of an the immunosuppressive activity. IL-6. phages or dendritic cells. including: renal support of this. MDSCs with different the differentiation of M1 or M2 MDSCs [107]. The ability to from murine tumors express high levels of metalloproteases. As an example. MDSCs CSF) prevents the differentiation in mature myeloid cells. A remarkable mice. to skew TAM differentiation toward a tumor-promoting type- teins: monocytic MDSCs (M-MDSCs) and granulocytic 2 phenotype [69]. In healthy individuals. In cules such as IFNγ. F4/ Because of their tumor-promoting activities. the growth of Lewis lung carcinoma was cancer (CD14. MDSCs characterized by both monocytic and granulocytic including the promotion of angiogenesis. Human MDSCs are generally identified as cells both M1 and M2 macrophages [6]. 96]. M. G-MDSCs suppress directly incorporate into tumor endothelium [108]. 99]. and this conversion is driven by tumor hypoxia [106].g. but utilizes up-regulation of iNOS and conditions. the expansion and function of MDSCs: one factor (e. macro. suggesting that essential role of paired-immunoglobulin receptors (PIRs) in several cellular subsets may exist. The balance phenotype (reported here in brackets) were identified in between PIR-A and PIR-B modulates MDSC polarization. In antigen-specific responses using mechanisms. The transcription tions they expand into MDSCs. The characterization associated with type-2 immune responses. progenitors differentiate in mature granulocytes. MDSCs have been factor CCAT/enhancer binding protein β (C/EBPβ) proved observed in cancer. lacking the express both Arg1 and iNOS. myeloid monocytes-colony stimulating factor (GM-CSF). The C5a subunit of the 110]. as well as production of immunosuppressive CD31 and VEGF receptor 2 (VEGFR2) and the ability to cytokines [82]. whereas in pathological condi. investigating the molecular phenotype of human MDSCs seems to be dependent from mechanisms behind MDSC differentiation. activate MDSCs [103].F4/80+ TAMs in the tumor site [105] Therefore. 102]. and able to suppress T cell activation [93. chronic infectious diseases. MDSCs are able morphology and the expression of Ly6 family glycopro.138 A. Further in MDSC-mediated immune suppression does not require the tumor microenvironment and in proangiogenic culture cell-cell contact. In tumor-bearing mice. that require prolonged cell-cell contact shown to be mediated by CD11b+GR1+ myeloid cells [109. 100]. melanoma iNOS and TNFα. differentiate into mature DCs and macrophages in vitro including MMP9 [10]. provided by pro-inflammatory mole- contributed to partially clarify the biology of MDSCs. M-MDSCs are CD11b+ Ly6G. and hepatocellu. where these enzyme are expression of markers of mature myeloid and lymphoid differentially expressed by M1 (iNOS) and M2 (Arg1) cells. of VEGF sequestered in the extracellular matrix. IL-10 to reduce IL-12 production by macrophages. Cells with similar phenotype. including agreement.CD33± CD11b± CD15±) [98]. two major subsets were identified on the basis of their relation exists between MDSCs and TAMs. macrophages requires cell-cell contact. It has been proposed that two signals are needed for within primary and metastatic tumors.CD11b± CD15±) [95. macrophage-released IL-12 [104]. demonstrated a the type of tumor born by the patient. polymorphonuclear neutrophils (PMNs) have received little . IL-1β. MDSCs expressing the common myeloid marker CD33. macrophage. by modulating their migration and ROS Tumor-Associated Neutrophils (TANs) Tumor-associated production [28]. On the contrary. In patients affected by various tumor types. tumor refractoriness to anti-VEGF therapy was the release of ROS. MDSCs contrib- lar carcinoma (CD14 ± HLA-DR low/. and CSF-1R (CD115) [6]. MDSCs accumulate [102]. In cancer patients. and to be the key player in the process of MDSC development autoimmunity. therefore showing a M1 phenotype.monocytes-colony stimulating factor (M-CSF). 94]. prostate cancer significantly retarded in PIR-B-deficient mice (Lilrb3−/−) (CD14. then MDSCs release Ly6Chigh cells with monocyte-like morphology. MDSCs acquire endothelial markers such as Arg1. MMP9 increases the bioavailability has been shown to be restricted to M-MDSCs [84]. The macrophages. MDSCs are 80.) [101]. differentiate into Gr1. 6) in the differentiation of MDSCs. Sica et al. have been identified in the blood. A recent study.HLA-DRlow/-) [97]. while G. precursors more IL-10 and are more potent down-regulators of of myeloid cells. Human ute to tumor growth also by nonimmune mechanisms. Recent studies have and a second signal. GM- spleen and peripheral blood.

as well as in TAMs [54]. carcinoma. which are associated It is also object of debate the existence of two distinct with a delay in tumor growth [54]. Fridlender and colleagues propose a new paradigm [123]. and lung [114].e. mainly involved in adaptive immunity. Other negative regulators of models using syngeneic tumor xenografts and the ortho. In p50 homodimer in macrophages. and target genes [122]. in murine lung cancer and mesothelioma inflammatory response [60]. Clinical (PAMPs). LPS-tolerant macrophages. both in TAMs and polarized TANs. namely N2-polarized TANs and granulocytic microenvironmental signals promoting accumulation of the MDSCs. or splenic MDSCs. It was suggested that N1. The NF-κB family consists of cancer [115. Similarly to macrophages. selectively acting on nals. In agreement. Neutrophils contribute to tumor and heterodimers associated with differential regulation of growth by promoting angiogenesis. induce p50 recruited from the spleen or whether they are blood-derived NF-κB homodimer activity [54]. IFN-γ). Fridlender et al. neutrophils acquire an antitumor pheno.and N2-type neutrophils are Interestingly. Two major influence not only immune and antimicrobial responses. and SHIP1 CTLs. suggesting that neutrophils immunoglobulin IL-1 receptor-related molecule/Toll-IL-1- participate to the antitumor activity of TGFβ blockade. while MDSCs mostly exhibit an Transducer and Activator of Transcription (STAT1) phos- immature morphology [120]. new evidence contradict this view. The classical pathway is stimulated by proinflamma- angiogenesis [112. colon. suppressor of tumorigenicity 2 (ST2). to become “N2 neutrophils”. we demonstrated that IL- the absence of specific markers. If high accumulation of nuclear p50 homodimers and defective TGFβ is blocked. revealed that its nuclear accumulation. and breast but not by TNFα itself [122]. 116]. TAM from p50−/− tumor-bearing mice neutrophils with a different degree of activation (i. TAMs display largely driven by TGFβ. most likely by the production of oxygen radicals. in that cytokines like IL-1 or microenvironment conditions such as Nuclear Factor κB (NF-κB) Several lines of evidence hypoxia can prolong PMN survival [111]. a TGFβ receptor important role in the control and extinction of the kinase antagonist. five members: NF-κB1 (p105/p50). signals [54]. To the extent they have been investigated. bronchoalveolar cell carcinoma. PGE2 and TGFβ. Also. is and poor outcome has been described in renal cell activated by certain members of the TNF cytokine family. that may form different homo- of TANs [117. The phages [60]. splenic myeloid unresponsiveness (tolerance) toward pro-inflammatory sig- cells (CD11b+).Role of Tumour-Associated Myeloid Cells (TAMCs) 139 interest by immunologists. interleukin 1 receptor accessory protein M (IRAK-M). In support to the existence of N2. 113]. However. In addition. Depletion of neutrophils by include the LPS-inducible splice variant of myeloid a specific anti-Ly6G antibody resulted in a significantly differentiation 88 (MyD88) termed MyD88s. NF-κB activation have been identified in disease and topic LSL-K-ras tumor model. not only mediates a status of blockade does not alter blood neutrophils. but actually plays as key regulator of M2-driven the intratumor activation of neutrophils. as well as by paid to TANs. imenting PMN depletion confirmed the detrimental nature RelA (p65). A detailed analysis of the neutrophils converted to an N2 phenotype by the tumor role of p50 NF-κB homodimer in macrophage functions microenvironment. and is mostly involved in innate immunity evidence indicate that the presence of TANs is a negative [122]. NF-κB2 (p100/p52). suggesting an authors investigated the effects of SM16. an alternative pathway of NF-κB prognostic indicator. Neutrophils are indicate the NF-κB system as a major regulator of the able to produce various cytokines and chemokines that can immune and inflammatory responses [121]. recognition of pathogen-associated molecular patterns including kidney. levels of Th1 cytokines (eg. other processes such as hematopoiesis. which are expressed by TAMs and N2 neutrophils within the tumors are granulocytic MDSCs promote M2-type polarized inflammation [124]. . preclinical studies exper. a recent report dimers has been observed in endotoxin tolerant macro- described the functional plasticity of neutrophils [7]. suggesting their tolerant phenotype. R8 (SIGIRR/TIR8). NF-κB activation in response to different pro-inflammatory type to become “N1 neutrophils” [7]. that seem to overlap for many characteristics. acting through inhibition of NF- characterized in Fridlender’s study have clear features of κB-driven M1-polarizing IFNβ production and Signal mature neutrophils. RelB and c-Rel. but signaling pathways control the activation of NF-κB [121. Also. By searching for the populations. breast. also based on their short life Molecular Determinants of TAMCs Functions span. respectively) IL-12high/IL-10low) and their splenocytes produce increased rather than two alternatively activated cell subtypes [119]. emphasize that TGFβ. in which resident TANs acquire a protumor phenotype. fully express cytokines characteristic of M1 macrophages (eg. depletion of neutrophils affected the activation of CD8+ suppressors of cytokine signalling 1 (SOCS1). activated or weakly activated neutrophils. phorylation [60]. Despite little attention has been tory cytokines. the single reduced effect of SM16. it cannot be determined if 10. cell proliferation. such as TNF-α and IL-1. A correlation between TANs infiltrate activation. 118]. TANs inflammatory reactions. these cells are present in various tumors. Accumulation of inhibitory p50 homo- metastasis [114]. wound healing. and 122].

it has been shown that HIF-1 activation MDSC differentiation and activation involves STAT1. by deciphering the molecular mechanisms macrophage polarization. 136. We have shown that hypoxic induction of HIF. provides pro-angiogenic. 142. by selectively up-regulating Signal Transducer and Activator of Transcription (STAT) the expression of the chemokine receptor CXCR4 [18]. which attracts MDSCs in the tumor. This cross-talk. Both iNOS and Arg1 are hypoxia has been shown to up-regulate NF-κB activity. repro- for both MDSC recruitment and pre-neoplastic lesions duces the effect of tumor microenvironment on MDSCs development. Johnson and colleagues proposed linking PIRs signalling with MDSC polarized activition. a recent study has and bind to the same hypoxic responsive element. follows distinctive kinetic profiles that suggest a greater involvement of HIF-1α in acute responses and of HIF-2α in Hypoxia Hypoxia is a main trait of solid tumours [2] and long-term responses [139]. HIF-1α is induced by Th1 cytokines differentiation into an M1 anti-tumor phenotype [107]. hypoxia in which in turn up-regulates HIF-1α levels [125].CD11b+ and F4/80+ subpopulations feature of most forms of solid tumor [1] and TAMs have [133]. 143]. 1α in TAMs influences the positioning and function of tumor cells. HIF-1α- functions of TAMCs are profoundly affected by activation deficient TAMs displayed defective capacity to suppress T of hypoxia inducible factors (HIFs) [128]. short-term presence and enhanced survival of neutrophils in exposure of murine bone marrow–derived macrophages to hypoxic tissues [111. the phenotype and lular carcinoma [140]. TAMs accumulate in tumor hypoxic marked defect in HIF-1α expression following deletion of areas and respond to the levels of hypoxia with a the NF-κB activity regulator IKKβ [125]. As a consequence. transcription program in which mitogenic. 131]. cellular response to hypoxia. the expression of HIF isoforms cancer-related inflammation. where they can stimulate tumor angiogenesis [110] and inducible factor 1 (HIF-1) has been shown to control the mediate tumor refractoriness to anti-VEGF therapy [134]. Hypoxia stabilizes HIF-1α. In a model of IL. mediates expression of the CXCR4 ligand CXCL12. and STAT6. TAMs and MDSCs influence the activation of adaptive NF-κB plays a key role also in the expansion and immunity. Conversely. Both in vitro and in vivo studies demonstrated and promotes their differentiation to TAMs [106]. functions by enhancing the expression of suppressive 1β–driven gastric inflammation and cancer it has been enzymes [6. in M1 macrophage polarization [139]. Furthermore. Interestingly. Noteworthy. Overall. a chemo. As a consequence. The trophic action of pathological hypoxia on preventing posttranslational hydroxylation and subsequent myeloid cells is also demonstrated by the increased degradation via the proteasome. STAT5. 135]. Sica et al. STAT3 is the member of the . they demonstrated the importance MyD88-NF-κB pathway for activate a distinct set of genes mediating unique biological MDSC accumulation in a mouse model of liver cancer [127]. 137]. triggered by hypoxic or pro-inflammatory signals. A microenvironment condition that appears to impact on kine involved in angiogenesis and cancer metastasis [132] and NF-κB signaling in TAM is hypoxia (low oxygen tension). In contrast. immunity [111]. More recently. 128]. HIF promotes pro-tumor behavior Accumulating evidence suggests that intersections and of leukocytes to the detriment of effective anti-tumor compensatory pathways may exist between HIF and NF-κB responses [10. In a model of breast cancer.140 A. that the IL-1β induced MDSC activation occurs through NF. HIF-2α was shown to regulate hypoxic areas are sites of accumulation for infiltrating TAM infiltration in murine models of colon and hepatocel- myeloid cells . p50. Hypoxia. Simon and colleagues reported that their combinatorial transcriptional partners. In line. that HIF-2α stabilization induced by Th2 cytokines leads to Ma and colleagues have demonstrated that PIR-A dependent type-2 polarization generating macrophages with pro-tumoral activation of STAT-1 and NF-κB pathways drives MDSCs activities. Hypoxia induces upregulation of the Bombina variegata been shown to accumulate in these areas where hypoxia 8 kDa protein (Bv8). Hypoxia has cell functions [141]. These results endorse the great potential divergent effects on cells of both innate and adaptive of HIF inhibition in cancer therapy. and pro-metastatic genes are up-regulated evidence of the close connection between immunity and the [130. HIF-alpha isoforms can differently regulate In contrast. Macrophages reveal a myeloid cells [129]. promotes their pro-tumor phenotype [10]. such as STATs HIF-2α directly regulate the expression of proinflammatory and IRF3 will likely contribute to fully clarify its role in cytokines [140]. STAT3. BCL3) and Arg1 genes. as it promotes inhibition of lymphocyte functional activation of MDSCs [103]. c-Rel. Hypoxia has a significant impact on systems in tumors [125. STATs are involved in several aspects of myeloid cell biology. via HIF-1α. hypoxic response. Gabrilovich and shown that activation of IL-1 receptor signalling is crucial colleagues demonstrated that hypoxia. stromal cells and TAMs. promotes recruitment of bone marrow-derived CD45+ myeloid The presence of many areas of hypoxia is a hallmark cells Tie2+.VEGFR1+. controlled by hypoxia. functions [138]. pro-invasive. This functional Further studies addressing the relative contribution of antagonism is due to a differential action on the iNOS and individual NF-κB members (p65. Even if HIF-1 and HIF-2 are apparently similarly regulated κB signalling pathway [126].

103. level of iNOS and rejected spontaneous mammary ically to Toll-like receptor 9 (TLR9)-expressing cells (B cells carcinoma by a process requiring adaptive immunity to and myeloid cells). TAMs lacking STAT6. 148]. binding protein 8 and 9 (S100A8/A9). Stat6−/− tumor– polarizing cytokine. 144]. as well as environment that sustains tumor growth [147. IFNγ-induced STAT1 Alternatively. In addition. macrophage polarization. Rolny and co-workers have reported that [29.Taking this reason. STAT3 is a prospective target for cancer therapy. Consistent with this. This display an M1 phenotype. and B-cell lymphoma masome activation and IL-1β production mediate activa- XL (BCL-CL) genes [82]. 30]. by skewing TAM polarization away from the M2-like to a generating a positive feedback loop that sustains MDSC tumor-inhibiting M1-like phenotype. Constitutive activation of STAT3 in tumor cells and in a well known anti-tumor drug. a potent . In contrast. For this to inhibit mammary carcinogenesis [159]. M1 and triggered innate response debulking large tumors An attractive means to solve this problem has been recently within 16 h [160]. 6]. while histidine-rich glycoprotein (HRG) promotes antitumor STAT1 is important for IFNγ-depending MDSC activation. MYC.Role of Tumour-Associated Myeloid Cells (TAMCs) 141 family mainly responsible for MDSC expansion. restored production of pro-inflammatory mediators associated immune cells and provoking strong antitumor (IL-12 and TNF-α) by infiltrating leukocytes and promot- immune responses. However. tion of protective immunity [153]. these induced a robust CD8+ T cell response against TAMs and proteins chemoattract MDSCs to tumor sites through a NF. a marker that has been found on genesis and tumor progression in several experimental some subsets of MDSCs where this pathway controls Arg1 tumor models [157]. [158] and there is evidence for antitumor activity of this surveillance in Stat6−/− mice facilitates survival against molecule in minimal residual disease [1]. MDSCs can produce S100A8/A9. as more evidence emerge and TGFβ expression [91. has been shown to re-educate TAMs bearing mice display a M1 phenotype. response via a TLR4-MyD88 pathway [152] and inflam- regulation of cyclin D. promoting asparaginyl endopeptidase family overexpressed by TAMs. and κB-dependent mechanism and potentiate ROS production metastasis [154]. led to a suppression of angiogenesis. Therapeutic Approaches Targeting TAMCs Targeting cytokines and cytotoxic proteins to tumors by means of gene modified cells represents a promising Activation of selected inflammatory programs provide strategy to treat cancer. resulting in reduced angio- engagement of CD124. combination of CpG plus an anti-IL-10 receptor Given that STAT3 is indispensable for hematopoiesis. Importantly. differentiation expansion [29. Ship1−/− mice display enhanced tumor implant growth [58]. tion. is able to revert TAM infiltrating myeloid cells creates the immunosuppressive polarization from M2-like to M1 phenotype. the host-produced expansion. 146]. with low level of Arg1 and high macromolecule delivers the STAT3-inhibiting siRNA specif. STAT3 also induce S100 calcium. In vivo administration of the drug activate tumor. with the block of STAT3 pathway. breast cancer model. could be used to deliver interferon-alpha (IFNα). 150. presented by dendritic cells and trigger a protective immune tiation of myeloid precursor cells. STATs activation extremely for the signaling pathways involved in the ‘switch’ of diverges in macrophage differentiation: STAT1 activation macrophage polarization states in the early stages of tumor results in M1 macrophage polarization. Recent results suggest that SHIP1 functions in vivo to repress M2 macrophage skewing. STAT3 151]. 145]. an antibody switched infiltrating macrophages from M2 to indiscriminate suppression of this pathway is not practicable. STAT6 is activated by the [156] or amino-bisphosphonate. synthetically linked to a CpG oligonucleotide [149]. Restored immuno. a member of the impair their differentiation into mature cells. STAT5 is involved in MDSC survival. tumor growth. it may be possible to develop new cytotoxic and inflammatory functions. especially in the case of M-MDSCs. Moreover. a pre. therapies aimed at preventing this and/or re-orientating M2- dominance of STAT3 and STAT6 activation results in M2 like TAMs in favour of a more antitumoral phenotype. It was recently shown that TEMs protection in a preventive or therapeutic setting [3. Moreover. It was reported that dying tumor cells can be cross activation stimulates myelopoiesis and prevents the differen. in vivo treatment with zoledronic acid. In analogy. 105. which promotes progression [1. inhibition of STAT3 activity. TLR9 activation synergizes cancer [161]. the proposed in a study utilizing a STAT3-targeting siRNA major mediator of IL-4 and IL-13 biological functions. S100A8 and S100A9 A recent work showed that DNA vaccine against the bind to receptors expressed on myeloid progenitors and M2-associated molecule legumain. immune responses and vessel normalization [155]. macrophages depletion has been obtained activation is fundamental in the up-regulation of Arg1 and in vivo with the use of clodronate-encapsulated liposomes iNOS [85. approach. which is associated with immune Direct activation with IFNγ a prototypical M1- suppression and tumor progression [6]. survivin. most likely through the up. leading to an effective required for IL-10 biological functions and gene transcrip- response. In spontaneous metastatic cancer via an IFN-γ-dependent mechanism [83]. ed tumour inhibition [147].

are able to eliminate MDSCs. cytokine with angiostatic and antiproliferative activity blood. PDE5 phos. Blocking IL-1 activity. The decrease in MDSC number correlated with [162]. Compounds under investigation for this ability of MDSCs could be essential in cancer patients undergoing belong to COX2 inhibitors. 32] protein. 167]. and NO-releasing non-steroidal anti- expanded anti-tumor T cells) immunotherapy. 141] Exploitation of cell tumor-homing aptitude for anti-tumor Engineereded TEMs [162] cytokine delivery Inhibition of TEM recruitment and activation Ang-2 antagonists [81] MDSC depletion Gemcitabine [166. Therapeutic strategy Therapeutic agents Refs loid cells TAM depletion Legumain based DNA vaccines [154] Clodronate [156] Trabectedin [170] Promotion of TAM switch from a M2-type to a M1-type IFNγ [158] phenotype TLR9 agonists + IL-10 [160] inhibition STAT3 inhibitors [147. MDSCs release the pro- patients with metastatic renal cell carcinoma showed the angiogenic protein Bv8 that surrogates VEGF in the efficacy of this compound in reducing MDSCs in peripheral stimulation of tumor angiogenesis [110]. such as The translational potential of MDSC research is dual. phosphodiesterase 5 (PDE5) active (vaccination) or passive (adoptive transfer of ex-vivo inhibitors. IL-1Ra Inhibition of MDSC accumulation and angiogenic activity Anti-Bv8 mAb [110] Interleukin-1 receptor antagonist. In fact. devoid of suppressive activity. 149] STAT6 inhibitors [161] p50 NF-κB homodimers [60] antagonists SHIP1 activators [58] Zoledronic acid [159] Inhibition of TAM suppressive function HIF-1 inhibitors [111. HIF-1 Inhibition of MDSC accumulation S100A8/A9 inhibitors [144] Hypoxia inducible factor-1. B cells. 164]. 149] ANG-2 Angiopoietin-2. SHIP1 Promotion of MDSC differentiation into mature cells Vitamin A [164. Preclinical evidence approach to contrast MDSC pro-tumoral activities consists support the use of IL-1 antagonists in treating human in the promotion of MDSC differentiation into mature cells metastatic disease. interesting candidate to restore immunosurveillance. It has myeloid progenitor cells into DCs and macrophages and also been reported that CD11b+ Gr1+ cells enhance tumor reduce MDSC accumulation [163.142 A. Conversely. COX2 Cyclooxygenase 2. devoid of suppressive functions sitol 5′-phosphatase 1. Recently. 165] Src homology 2-containing ino. Prevention of neutrophils recruitment to tumors CXCR2 antagonists [119] Bv8 Bombina variegata 8 kDa Blockade of M2-type and N2-type polarization. It has tumors [77]. thanks to the preferential homing of TEMs to the improved-antigen-specific T cell responses [165]. it was shown that the effect is also mediated by the decrease Vitamin A metabolites stimulate the differentiation of of MDSC accumulation and suppressive activity [83]. inhibition TGFβ inhibitors [7. [82] NSAISs nitric oxide-releasing PDE5 inhibitors [82] non-steroidal anti-inflammatory NO-releasing NSAIDs [82] drugs. STAT6 inhibitors [161] phodiesterase 5. without affect- The immunosuppressive activity of MDSCs could be ing T cells. NK cells. gemcitabine. In this situation. A possible inflammatory drugs (NSAIDs) [82]. S100A8/A9 S100 calcium- binding protein 8 and 9. and macrophages [166. CXCR2 chemokine of MDSC suppressive functions (C-X-C motif) receptor 2 . been reported that some chemotherapeutic drugs. STAT3 inhibitors [147. mainly IL-1β. elimination function. Sica et al. NO-releasing Inhibition of MDSC suppressive functions COX2 inhibitors. Because Bv8 is Table 1 Anti-cancer strategies targeting tumor-associated mye. A clinical trial refractoriness to anti-VEGF antibody (bevacizumab) treat- testing the effects of all-trans-retinoic acid (ATRA) in ment [109]. Vitamin A represent an reduces both metastasis and tumor growth [168]. 167] TLR9 Toll-like receptor 9. exploited to inhibit immune responses in autoimmune Another strategy is aimed to inhibit MDSC suppressive diseases and organ transplantation.

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Sergi Sergi L. formation and a mesenchymal population of pericyte progeni- Hence. profile and the functional properties of TAMCs and it is logic patients are already immunocompromized individu. body or a CXCR2 antagonist has been successfully tested by Ministero Università Ricerca (MUR). Miyamoto T. Mantovani A (2010) Macrophage plasticity and insufficient to eradicate myeloid cells support to tumor interaction with lymphocyte subsets: cancer as a paradigm. Sica A (2010) Role of tumour-associated macrophages in accumulation is suppressed. Locati M (2009) Tumor-associated macrophages and the related myeloid-derived TANs.Role of Tumour-Associated Myeloid Cells (TAMCs) 143 also important in MDSC mobilization and homing to the gies able to target different myeloid cell populations. Sampaolesi M. Kim S. Italy. Interestingly. Allavena P. 5. and diversity. Cancer Cell 8:211–226 to eradicate myeloid cell support to tumor growth. august 8th. Fondazione Cariplo. 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