Cancer Microenvironment (2012) 5:133–149

DOI 10.1007/s12307-011-0091-6


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: towards mechanisms and molecules driving the protumoral
skewing of TAMCs.
A. Sica
e-mail: 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.

Recent studies have highlighted that striking similarities TAN depletion represents a potential therapeutic exist among mechanisms governing both the transcriptional approach for cancer cure [169]. Concluding Remarks Worthen GS. 6. Sun J. in pre-clinical experimentation [119]. MDSCs and TANs display distinct specialized of myeloid cells in the promotion of tumour angiogenesis. Therefore. with a promote the protumoral traits of different TAMC popula- switch from N2. However. 172]. tions. given that activated neutrophils can kill (N1 vs N2) may share common constituents [120]. TAMs. Vaupel P. Fridlender ZG. Politi LS. Nature 404:193–197 populations. tions of either macrophages (eg. TAMCs 12. Italy. De Palma M. Kroemer G. this is an interesting candidate for cancer simultaneously. it scenario suggests that key mechanisms may converge to would be of interest to modulate TAN phenotype. Allavena P. 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. M1 vs M2) or neutrophils Alternatively. Galli R. Balkwill F (2008) Cancer- driven accumulation of TAMs limits the influx of neutrophils related inflammation. Nat growth. neutrophils are recruited to the cancerrelated inflammation. Zitvogel L (2011) The appear to constitute a robust system and the functional dendritic cell-tumor cross-talk in cancer. Naldini L (2005) Tie2 identifies a hematopoietic in the absence of TAMs. Nature 454:436–444 in solid tumors by a yet unidentified mechanism. Sica A (2010) Macrophages. New evidence also suggest that TAMCs reciprocally suppressor cells as a paradigm of the diversity of macrophage influence their protumoral differentiation. New therapeutic strategies have been aimed at targeting Janus face of dendritic cells in cancer. Locher C. Lewis CE (2008) The role TEMs. 10. the elimination of TAMs alone may be insufficient tors. 13. under the “remote activation. 22:231–237 methylene–biphosphonate) and Yondelis® (trabectedin) [156. Traver D. leading to accumulation of protumoral TAMC myeloid lineages. However. Biswas SK. Cancer Metastasis Rev 26:225–239 3. Hum Immunol 70:325–330 control” of T and B lymphocytes [3. Ma Y. Kapoor V. Mantovani A. cancer-associated myeloid cells. Chaput N. Exp Oncol 32:153–158 tumor providing a secondary source of MMP-9. 2. Mantovani A. cancer: balance. Sica A. Zitvogel L (2008) The sis). If TAM 4. innate immunity and reduce or eliminate TAM recruitment have been developed.towards N1-polarization. Cheng G. potentially lethal. 11. Akashi K. It appears therefore necessary to identify strate. Ministero della Salute and by Regione Piemonte (project number 331. Aymeric L. Murdoch C. Ling L. Immunol 11:889–896 . Venneri MA. Inhibition of Acknowledgments This work was supported by Associazione CXCR2-mediated PMN chemotaxis with a specific anti. Curr Opin Immunol 23:146–152 elimination of a single myeloid population may be 13. tumor site. Italy. Curr Opin Immunol Two agents able to eliminate TAMs are clodronate (dichloro. tolerance. Several strategies aimed to 1. TANs provide alternative paracrine lineage of proangiogenic monocytes required for tumor vessel support for tumor angiogenesis and progression [171]. as well as overlapping activities (eg. a complete ablation of neutrophils is not desirable. 72. therapy. MDSCs and 9. TEMs. Nevertheless. Italiana Ricerca sul Cancro (AIRC). which include TAMs. Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. Sica A. becoming clear that pathways promoting polarized func- als. Mantovani A. A more manageable therapeutic strategy can target neutrophils recruitment to tumors. J Clin Invest 117:1155–1166 7. The description of the pivotal role of TGFβ in the promotion of a protumor phenotype of TAN suggests that therapies contrasting this References cytokine could contribute to re-educate neutrophils in the tumor microenvironment [32]. a recent study showed that the CCL2. thus potentially offering common target/s to thera- this plan would lead to the generation of highly cytotoxic peutically affect the protumoral networks established by cells and could result in excessive tissue damage. since onco. 2009). Mayer A (2007) Hypoxia in cancer: significance and 170]. Conforti R. Muthana M. Sica A. Spatz A. Oncogene 27:5920–5931 single myeloid populations (Table 1). Weissman IL (2000) A expansion and functional skewing of different myeloid cell clonogenic common myeloid progenitor that gives rise to all populations. Cancer Cell 16:183–194 Recent results indicate that tumour development promotes 8. impact on clinical outcome. This tumor cells through the release of toxic substances. Coffelt SB. Albelda SM (2009) Polarization of tumor- associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Viaud S. angiogene. Nat Rev Cancer 8:618–631 functions. Garlanda C.

Zhou A. Gerard C. Palma MD. Nat Immunol 9:186–193 JD (2008) Modulation of the antitumor immune response by 45. enously derived IFN. 111:5457–5466 Schlessinger J. Macrophage polarization: tumor-associated macrophages as a Mantovani A. Sorg C. Wells C. Naldini L (2007) Identifica. 41. Doglioni C. J Immunol 140:3640–3645 myeloid-derived suppressor cells in tumor-bearing mice. Gouon-Evans V. Lambris dependent kinases in macrophages. Mamidi S. Benencia F. Nat Immunol 9:1225–1235 consist of two principal subsets with distinct migratory proper- 29. Porta C. Henson PM. Zhang J. Blood 44. ties. Schioppa T. Welford AF. Boraschi D. Ostrand-Rosenberg S. of type I interferon-induced Jak-STAT1 signaling by calcium- Lichtsteiner SK. Yu X. J Immunol 141:180–188 Serio CD. Keshav S. Gessler M. Melillo G. Mizutani K. Shimaoka T. De Palma M. 14. Flavell RA. Mantovani A (1983) Regulation of the Bernaudin JF. Shono Y. Gil-Henn H. Mayaud C. Scielzo C. Characterization of lipopolysaccharide-induced macrophage Matsushima K (2008) Chemokine-mediated rapid turnover of gene expression. Trends chemokine receptor CXCR4 by hypoxia. Yu B. Wang L. Ivashkiv LB (2008) ‘Tuning’ 28. Kang YJ. Activation of urokinase plasminogen activator and its receptor Muller-Molinet I. Smith MS. Nagaraj S. Luetteke N. Nat Rev Cancer 4:71–78 32. Nat Rev Immunol 8:958–969 Cancer 4:540–550 37. Tazzyman S. Nat Rev Immunol 10:554–567 of tumor-associated macrophages. Roth J. Coffelt SB. Semin Cell Biol 25. Balsari A. Mantovani A (2008) The The polarization of immune cells in the tumour environment by inflammatory micro-environment in tumor progression: the role TGFbeta. Philippe C. Mazzieri R. Koutoulaki A. Gordon S. Sozzani S. Yurochko AD (2009) NF- (2008) Inhibition of dendritic cell differentiation and accumula. Ji JD. Ravasi T. Hume DA (2002) Generation of trafficking via the chemokine receptor CCR2. Jung S. Bui MM. Fujiyama Y. Locati M. Grimmond S. Catterall JF. Foldi J. Venneri MA. Tannenbaum CS. Sanjabi S. Saccani S. 47. Foell D. J Immunol 180:6553– metastasis. Feng Z. 31. J Immunol 168:44–50 Expression of Tie-2 by human monocytes and their responses 40.144 A. Chan G. Bernasconi S. Salmona M. Nacken W. Bellocq A. Strunk RC tion of proangiogenic TIE2-expressing monocytes (TEMs) in (1988) Differential regulation of gene expression during macro- human peripheral blood and cancer. Antoine M. Flahault A. Joyce JA. Ponzoni M. Blood 109:5276–5285 phage activation with a polyribonucleotide. Smith PM. 111 J Exp Med 176:287–292 18. Chan G. Stein M. Sica A (2002) Rapisarda A. Markiewski MM. Tietzel I. Kakimi K. Wu I. Chung AY. Freeze HH. 35. Kawsar HI. Sica et al. 43. Milleron B. Goerdt S (2008) Activation of a axis is essential for macrophage infiltration in a prostate cancer TGF-beta-specific multistep gene expression program in mouse model. Polentarutti N. J Immunol reprograms monocyte differentiation toward an M1 macrophage. Tateya T. Uranchimeg B. Baud L. Nucera S. Watkins SK. Sinha P. Gabrilovich DI 46. Smith MS. potently enhances murine macrophage mannose receptor activ- neoplastic and neoplastic lung tissue. Nguyen AV. antimicrobial peptide regulates tumor-associated macrophage Aderem A. Licona-Limon P (2010) 16. Kageyama R. Riches DW. macrophage growth factor CSF-1 in mammary gland develop. Zhang JJ. kappaB and phosphatidylinositol 3-kinase activity mediates the tion of myeloid-derived suppressor cells in cancer is regulated by HCMV-induced atypical M1/M2 polarization of monocytes. Edwards JP (2008) Exploring the full spectrum of 19. Jia X. Gordon S (1992) Interleukin 4 Macrophage inflammatory protein-1 alpha expression in non. Lewis CE (2011) 42. Hirsch SA. Crit Rev Oncol Hematol 33. Sica A (2003) Regulation of the paradigm for polarized M2 mononuclear phagocytes. Forest A. 6:377–384 Zonari E. DeAngelis RA. Bivins-Smith ER. Taylor PR (2005) Monocyte and macrophage 66:1–9 heterogeneity. a model for diversity in the innate immune system: macrophage heterogene- tumorigenesis. Science Neutrophil alveolitis in bronchioloalveolar carcinoma: induction 220:210–212 by tumor-derived interleukin-8 and relation to clinical outcome. Kzhyshkowska J. Allavena P. J Mammary Gland Biol Neoplasia (2008) Integrated regulation of Toll-like receptor responses 7:147–162 by Notch and interferon-gamma pathways. Okoro C. Hu X. Matta B. Sica A. PLoS ONE 5:e10993 ity arises from gene-autonomous transcriptional probability of 24. Bottazzi B. Tozer GM. Solinas G. Mukaida N. Vogl T. Pienta KJ (2011) M. J Exp Med 198:1391– Immunol 23:549–555 1402 36. McIntyre TM. Wrzesinski SH. Gooi L. Gyetko MR. Popova A. Crestani B. Park-Min KH. Acero R. Nebuloni M. Nat Rev macrophage activation. 703 Zheng QY. Doni A. J Exp Med 205:2235–2249 Virus Res 144:329–333 30. Kannookadan S. Konishi T. Nat Rev Immunol 5:953–964 17. Ghosh SK. 15. Balkwill F (2004) Cancer and the chemokine network. Coukos G. Yurochko AD Srikrishna G (2008) Proinflammatory S100 proteins regulate the (2008) Transcriptome analysis reveals human cytomegalovirus accumulation of myeloid-derived suppressor cells. Riches DW (1995) Signalling heterogeneity as a contributing to angiopoietin-2. Stonehouse-Usselmann E. Immunity 29:691– 23. Pucci F. Webster S. Neoplasia 13:23–30 mature macrophages requires glucocorticoid-mediated surface 21. Cadranel J (1998) macrophage content of neoplasms by chemoattractants. Chen J. Pucci F. The role of endog- 26. Koerner TJ. Sud S. Weinberg A (2010) An 39. Talmadge JE. Kurachi M. Pollard JW (2009) Microenvironmental regulation of expression of TGF-beta receptor II. Wainwright BJ. Harris N. Allavena P. Kitabatake M. Naldini L. Mosser DM. J Immunol 178:7405–7411 factor in macrophage functional diversity. Ueha S. Jansen MM. Lin EY. Immunity 19:71–82 Ortiz M. J Clin Investig Immunol 175:342–349 27. Jiang C. Cheng P. Sawanobori Y. Vago L. Reid AC. Mori A (1996) 34. Zeng C. Virchows Arch 428:107– ity: a marker of alternative immunologic macrophage activation. Nat Rev Cancer 9:239–252 6565 22. Geissmann F. Suttles J TIE2-expressing macrophages limit the therapeutic efficacy of (2005) Macrophages sequentially change their functional pheno- the vascular-disrupting agent combretastatin A4 phosphate in type in response to changes in microenvironmental influences. Corzo CA. Ivashkiv LB ment and tumor progression. Hamilton TA (1988) Abe J. Baron R. Ochsenreiter 20. Pollard JW (2004) Tumour-educated macrophages promote Am J Pathol 152:83–92 tumour progression and metastasis. Jin G. Ghezzi P. Lewis CE (2007) individual inducible genes. Littman DR (2003) Blood monocytes complement. Murdoch C. Ricklin. Mantovani A. Stout RD. Katoh H. Remigio LK. Biswas SK. Fisher M. Han J. J mice. Underhill DM. Okabe H. Tassiulas I. S100A9 protein. Pollard JW (2002) The 38. Bivins-Smith ER. Biziato D. 181:4666–4675 J Immunol 181:698–711 . Gratchev A. Saccani A.

Kirilovsky A. Cancer Cell 7:411–423 phages in antitumor immune responses. Hu XB. Chen YY. Budhu A. Vasquez L. Andreu P. Schiarea S. Comoglio PM. Kikutani H. Shah SP. De Baetselier P. Di Liberto D. Proc Natl Acad Sci U S A 106:14978–14983 X. Saccani A. Sica A. (TEMs): novel targets and vehicles of anticancer therapy? Zinzindohoue F. Pages F (2006) Type. Campo E. Feng L. Johansson M. Coussens LM (2005) De novo Zheng MH. Wang YC. Ghezzi P. of M2-polarized tumor-associated macrophage in pancreatic Dynamic. Abastado JP. Carmeliet P (2010) Malignant cells fuel 72. 77. Markowitz D. Delabie J. Ostrand- 55. Mataki Y. Feng F. Lam V. Rosenberg S (2007) Cross-talk between myeloid-derived sup- Rimoldi M. Coussens LM (2009) CD4(+) T cells regulate generation of alternatively activated macrophages. De Palma M. Coussens LM (2010) FcRgamma activation Dieli F. Fabbri M. Jaffe ES. Gascoyne RD (2010) Tumor-associated macro- 50. De Palma M. van 185:642–652 Damme J. Tubbs RR. J Immunol 186:4183–4190 . Hoylaerts M. 49. Lumeng CN. Sica A. Maemura K. Sanchez-Cabo F. Naldini L. Tosolini M. Rauh MJ. Trajanoski Z. Biswas SK (2010) Macrophage 61. Cignetti A. 74. 71. Mui A. de Visser 60. Bunt SK. Lam J. Natoli G. J Immunol 180:2011– 65. Chittezhath M. Trends Immu. Luttun A. Sica A (2006) p50 Transcriptional profiling of the human monocyte-to- nuclear factor-kappaB overexpression in tumor-associated mac. Xiang R. Li NF. Nayar T. Truitt M. Lewis CE (2008) Plasticity of phages and survival in classic Hodgkin’s lymphoma. Olson P. J Surg Res tissue macrophages during high-fat diet–induced obesity in mice. Cancer Cell 17:121–134 tion are related processes orchestrated by p50 nuclear factor 76. M2-like remodeling phenotypes of CD11c + adipose cancer. Scholz cells within human colorectal tumors predict clinical outcome. Liguori M. Vanhoutte D. N Engl J macrophage function during tumor progression: regulation Med 362:875–885 by distinct molecular mechanisms. Kumanogoh A. Han H (2011) Notch carcinogenesis promoted by chronic inflammation is B lympho- signaling determines the M1 versus M2 polarization of macro. Sica A. J Immunol 177:7303–7311 resistance. J Biol Chem 284:34342–34354 54. Roca H. J type. KE. Clements VK. Lenz G. Qin HY. Natsugoe S. Frid. Conrotto P. Charles K. A (2009) Tolerance and M2 (alternative) macrophage polariza. Porta C. J Immunol 179:977–983 Biol 18:349–355 70. Schioppa T.Role of Tumour-Associated Myeloid Cells (TAMCs) 145 48. Saltiel AR (2007) Obesity induces a cells polarize macrophages toward a tumor-associated pheno- phenotypic switch in adipose tissue macrophage polarization. Vago 68. Lopez DM (1996) The altered Zammataro L. Sly LM. de Visser KE. Porta C. Reiss Y. Caione L. Tal AO. Noma H. Hanahan D (2010) Cancer- associated macrophages. Wilson J. Immunity pulmonary metastasis of mammary carcinomas by enhancing 23:361–374 protumor properties of macrophages. dependent manner. Coffelt SB. Chan WC. Solinas G. Wang kappaB. J Exp Med 205:1673–1685 associated fibroblasts are activated in incipient neoplasia to 57. Ueno S. Lopez-Collazo E (2009) Endotoxin tolerance: new Muller-Hermelink HK. Blood 115:2264–2273 Immunol 40:2131–2133 58. RM. Pluddemann 2017 A. Sierra JR. Huxham L. Han G. Pesce S. Vecchi A. 73. Krystal G (2005) SHIP represses the Kolhatkar N. Kubo suppress T cell activation and to promote regulatory T cell F. PLoS ONE 4:e7965 progression are enhanced by Sema4D produced by tumor. Tan T. Sud S. Puaux AL. Brys L. Liang L. density. Lee T. 52. Nebuloni M. Eur J hepatocellular carcinoma. Chiabrando C. Tjwa M. Biswas SK. Cancer Res 70:4840– 75. cyte dependent. Bennett G. Dong GY. tasis by modulating the tumor immune microenvironment in a Tamagnone L. Nebuloni M. Rosenwald A. Porta C. Cepero V. De Palma M. He F. J Exp Med 183:1323–1329 M2-polarization. Tawfik D. DeNardo DG. Camus M. influencing tumor cell motility. Cancer Cell 17:135–147 Dewerchin M. molecules and clinical significance. Ying C. Murdoch C. Polentarutti N. Staudt nol 30:475–487 LM. Iqbal J. Bottazzi B. Pienta KJ (2009) 10 mediates defective IL-12 production and NF-kappa B CCL2 and interleukin-6 promote survival of human CD11b + activation in tumor-associated macrophages. Weisenburger DD. Wong SC. Craig MJ. Sinha P. Erez N. Schmidt T. Albelda SM. Mantovani A. Mantovani A (2006) L. J Immunol peripheral blood mononuclear cells and induce M2-type macro- 164:762–767 phage polarization. Raes G. Lam KP. Andreu P. Wang XW (2006) The role of cytokines in polarization to a unique phenotype driven by B cells. Diabetes 59:1171–1181 Jones SJ. Plaisance S. Saccani A. Balkwill FR (2006) Ovarian cancer 51. Obin MS. Muthana M. Affara NI. Gordon S. Pereira C. Mlecnik B. Naldini L (2009) Tie2-expressing monocytes Lagorce-Pages C. 67. Bottazzi B. Sica regulates inflammation-associated squamous carcinogenesis. Hagemann T. J Leukoc Biol 80:1197–1213 Immunol 40:2296–2307 62. Sham A. Bast MA. Berger A. tumoricidal capacity of macrophages isolated from tumor. Jonckx B. Korets LV. Martinez FO. Strissel KJ. Farinha P. van Geyte K. Sica A. Biochim Biophys Acta 1796:5–10 man WH. Shaul ME. Lievens D. Liu XW. Porta C. Eur J mitogen Gas6. Shalova I. Braziel mechanisms. Rubino L. Bodzin JL. Mancino A. Shinchi H. Dinapoli MR. Semin Cancer a type 2 response. Cancer associated fibroblasts promote tumor growth and metas- Piacibello W. Kurahara H. Plate KH. Giordano S (2008) Tumor angiogenesis and 4T1 murine breast cancer model. Allavena P (2010) Tumor-conditioned macro- bearing mice is related to reduce expression of the inducible phages secrete migration-stimulating factor: a new marker for nitric oxide synthase gene. Calderon CL. Takao S (2009) Significance expansion. Larghi P. Mantovani A (2000) Autocrine production of IL. Gordon S. Allavena P. Barreto JB. Delaney A. Bruneval P. Sakoda M. Steidl C. Mantovani A. Pasqualini F. Cugnenc PH. Costes A. Reisfeld RA (2009) 56. Welford AF. Varsos ZS. Riboldi E. Colombo MP. Biswas SK. Burke F. A. Rimoldi M. Luo Y. Junankar S. Lutgens orchestrate tumor-promoting inflammation in an NF-kappaB- E. macrophage differentiation and polarization: new molecules rophages inhibits M1 inflammatory responses and antitumor and patterns of gene expression. J Immunol 176:5023–5032 Clin Invest 117:175–184 66. Loges S. Corso S. Kajiji TS. Totaro MG. Ho V. Cancer Cell 16:91–102 59. J Immunol 53. Cancer Res 66:11432–11440 69. Wind P. Rimsza LM. Biswas SK. and location of immune 78. Cook JR. Ghisletti S. Borgel D. Biswas SK. Tawfik D. Liao D. DeNardo DG. Liang YM. Arron ST. Mantovani A. Minchinton AI. Greenberg AS. Lewis CE Science 313:1960–1964 (2011) Angiopoietin 2 stimulates TIE2-expressing monocytes to 63. 64. Connors JM. Mantovani A (2008) pressor cells and macrophages subverts tumor immunity toward Macrophage polarization in tumour progression. Locati M (2010) Convergent tumor growth by educating infiltrating leukocytes to produce the pathways of macrophage polarization: the role of B cells. 4849 Korets L. Locati M. Kulbe H. Galon J. Pucci F.

Calabrese F. Fingleton B. Gabrilovich DI (2007) Altered recogni.146 A. van Beynen J. Coffelt SB. Gabrilovich DI (2001) Increased bearing host directly promotes tumor angiogenesis. Matsui S. Rodriguez PC. Mamura M. Van Ginderachter blood of melanoma patients with modulation by a granulocyte- JA (2008) Identification of discrete tumor-induced myeloid. De Palma M (2009) A distinguishing gene derived suppressor cells in renal cell carcinoma are a subpopu- signature shared by tumor-infiltrating Tie2-expressing mono. Huang B. Movahedi K. Pan PY. Iero M. sor cells in renal cell carcinoma patients: a mechanism of tumor Biswas SK. Greten TF. Van den Bossche J. Hansson J. J 99. Marigo I. Cancer function. Bronte V. Sherman S. Lin HC. Naldini L. Yang R. J Exp Med 207:2439– prevents tumor recurrence. Blood 114:901–914 Mier J. 80. Srivastava MK. Cozzi E. Wang CH. Gupta K. Poschke I. Ballmaier M. Plate KH. Nat Med 13:828–835 102. Gabrilovich DI (2005) STAT1 signaling regulates Res 66:1123–1131 tumor-associated macrophage-mediated T cell deletion. myeloid-derived suppressor cells in hepatocellular carcinoma Herber DL. Immunity 34:385–395 93. Li Q. Di Sierra R. Nagaraj S (2009) Myeloid-derived suppressor 98. J Cancer 84. Atkins MB. Mariani L. Cancer 105. De Palma M. Mandruzzato S. Guilliams M. Ostrand- 90. Pilla L. Quiceno DG. Pagano F. Qin R. Pisarev V. Takai T. Borsellino G. Prostate 70:443–455 82. Basso G. Ma G. Wang CL. Rodriguez P. Van den Bergh cation of a new subset of myeloid suppressor cells in peripheral R. derived suppressor cells: the blessing and the curse of Chen SH (2011) Paired immunoglobin-like receptor-B regulates morphological and functional heterogeneity. Kruger C. Valenti R. blood “resident” monocytes. Sinha P (2009) Myeloid-derived suppres. Lin Y. English NR. nol 174:4880–4891 Donaldson DD. monocytes and augments their inherent proangiogenic functions. (2005) Boosting antitumor responses of T lymphocytes CD83. Clark JI. Sato AI. J Exp Med 201:1257– 101. Cancer Res 65:3044–3048 Angiopoietin-2 regulates gene expression in TIE2-expressing 97. Scholz A. beta production and myeloid cells are an effector mechanism McCaffrey JC. Sinha P. De Palma M. Huber V. Cai Z. Gabrilovich DI (2011) Molecular mechanisms (2006) CD80 in immune suppression by mouse ovarian regulating myeloid-derived suppressor cell differentiation and carcinoma-associated Gr-1 + CD11b + myeloid cells. Hanson EM. Signoretti S. Gabrilovich DI (2010) HIF-1alpha regulates through which CD1d-restricted T cells block cytotoxic T function and differentiation of myeloid-derived suppressor lymphocyte-mediated tumor immunosurveillance: abrogation cells in the tumor microenvironment. Lee KY. Gabrilovich DI. Wahl SM. Bunt SK. Gabrilovich DI (2010) Myeloid-derived suppressor 108. Berzofsky JA (2003) Transforming growth factor. Nagaraj S. Gallana K. Paul WE. Filipazzi P. Condamine T. Sica A. and DC-sign. Lowell CA. Mougiakakos D. J Leukoc Biol 85:996–1004 regulatory cells and T-cell anergy in tumor-bearing host. 9:162–174 Yu CT. Park JM. Biziato D. Dietz AB (2010) Immunosuppressive CD14 + HLA-DRlow/- Cancer Res 70:5270–5280 monocytes in prostate cancer. Moi D. Immunity 32:790–802 89. Letterio 106. Roby KF. Quiceno D.and 83. Divino CM. Canese P. Fernandez A. Bromberg J. J derived suppressor cell subpopulations with distinct T cell. Sinha P. Ledbetter S. Cancer Res 69:1553–1560 cytes. Bronte V (2010) Tumor- cells inhibit T-cell activation by depleting cystine and induced tolerance and immune suppression depend on the C/ cysteine. Battistini L. J Immunol exogenous genes to tumor angiogenesis by transplantation of 166:678–689 genetically modified hematopoietic stem cells. Eur J Immunol the suppressive function and fate of myeloid-derived suppressor 40:2969–2975 cells. Cotter MJ. Viola A cells in melanoma patients are Stat3hi and overexpress CD80. Yutzy WHT. cells in human cancer. Gabrilovich DI (2008) Subsets Res Clin Oncol 136:35–45 of myeloid-derived suppressor cells in tumor-bearing mice. Yang L. J Immunol 182:4499– CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes 4506 in patients with advanced-stage non-small cell lung cancer. Naldini L (2003) Targeting mechanism of immunosuppression in cancer. Kasic T. Venneri MA. Ormandy LA. Zabaleta J. Parmiani G. Levy DE. Solito S. Pucci F. Mesa C. Sica et al. Lehner F. Kusmartsev S. McCaffrey TV. Nat Med 9:789–795 95. Korangy F (2008) A new population of 87. Lin PC (2004) Expansion of 94. Cancer Res 70:68–77 EBPbeta transcription factor. Padhya T. Lewis CE (2010) evasion. 1268 Manns MP. Beschin A. Vuk-Pavlovic S. Reiss Y. Hernandez C. DeBusk LM. Zhang Y. Nonis A. Condamine T. Rodriguez PC. Ostrand-Rosenberg S (2010) Myeloid-derived suppressor Zanovello P. Ochoa AC (2005) Arginase-producing myeloid suppres- 81. inducible nitric oxide synthase-expressed CD11b+/CD14/CD15+/ sor cells: linking inflammation and cancer. Collazo M. Rivoltini L (2007) Identifi- 85. McDermott D. Nagaraj S. Masucci GV. 79. Hoechst B. P. Cho HI. Almand B. J Exp Med 198:1741–1752 2453 92. Kuo HP (2009) Population alterations of L-arginase. Nagaraj S. macrophage colony-stimulation factor-based antitumor vaccine. Iafrate M. Bicciato S. Gysemans C. Falisi E. Clin Oncol 25:2546–2553 suppressive activity. Terabe M. Nikitina E. Kang L. Green-Jarvis B. Gri G. Fukuda K. Sonda N. Szumlanski CL. Clements VK. Ugel S. Hernandez C. Murdoch C. cells as regulators of the immune system. 88. Chen W. Prayer-Galetti T. Nat Rev Immunol Chu Y. Youn JI. Lu L. Zhao X. Urbich C. 107. Carbone DP. Clements VK. Roden RB 103. O’Neill A. Cancer J 16:348–353 Shyr Y. Roca C. Tal AO. Kuo CH. Lin SM. Cancer Res 70:4335–4345 infiltrating human prostate cancers. Liu CY. Ko HW. Bosio E. Venneri MA. Cheng JJ. Celis E. Ochoa AC (2009) Arginase I-producing myeloid- Serio C. Patel S. Chen SH (2006) Gr-1 + CD115+ immature myeloid suppressor cell cross-talk by signaling through Toll-like receptor suppressor cells mediate the development of tumor-induced T 4. Divino Rosenberg S (2009) Inflammation enhances myeloid-derived CM. Marigo (2010) Immature immunosuppressive CD14 + HLA-DR-/low I. Youn JI. Carbone DP. Schneck J. patients induces CD4(+)CD25(+)Foxp3(+) T cells. Wu YC. Zabaleta J. Ostrand-Rosenberg S. Atkins M. Trends Immunol 32:19–25 Res 66:6807–6815 104. lation of activated granulocytes. Corzo CA. Noben-Trauth N. Gastroenter- tion of antigen is a mechanism of CD8+ T cell tolerance in ology 135:234–243 cancer. Cancer Cell production of immature myeloid cells in cancer patients: a 6:409–421 . Gabrilovich DI (2010) The biology of myeloid. De Baetselier P. Pan PY. Bulur PA. Feng PH. Chung FT. Eisenstein S. Wang YM. J Immu- 91. Kiessling R 86. suggests common functions and developmental relationships. myeloid immune suppressor Gr + CD11b + cells in tumor- Knight SC. Matrisian LM. Pratt B. Ernstoff MS. Blood 111:4233–4244 100. Liu YH. Immunol 181:5791–5802 Castelli C. Youmans A. Kinarsky L. Dolcetti L. Zea AH. and embryonic macrophages 96. Youn JI.

Zhong C. Mantovani A (2008) Cancer related timate the power of a neutrophil. Liu P. Nordsmark M. Giaccia AJ (2007) HIF 121. Ho C. Cui G. 135. Callaghan MJ. Sendo F. Cancer Res 70:7465–7475 Betz KS. Johnson RS. J Mol Med J Pathol 167:627–635 112. Johnson links innate immunity to the hypoxic response through tran. Ferrara N (2007) Tumor refractoriness to anti. Yu L. Rubinstein MP. Petritsch C. Wu X. Schachtrup C. Tada M. Meng YG. Ebbert JO. Lo-Man R (2009) 267:204–215 Coactivation of Syk kinase and MyD88 adaptor protein path. 143. Print C. Mantovani A. Melton LJ. Melillo G. Immunity 31:698–700 inflammation: the macrophage connection. Iliopoulos O. Zhang X. Murdoch C (2005) Macrophage responses to hypoxia: 111. O’Neill LA. Mantovani A (2009) Never underes. Johnson RS. 118. Taylor LS. Gerber HP. Rueda function. Sica A. Kleinman ME. Silberstein S. Gerez J. J enhancer-binding protein beta. Donskov F. Johnson RS and progression. Ross J. von der Maase H (2009) Presence of intratumoral neutrophils HIF1alpha induces the recruitment of bone marrow-derived is an independent prognostic factor in localized renal cell vascular modulatory cells to regulate tumor angiogenesis and carcinoma. Kobayashi M. Bais C. Scand J Gastroenterol 46:156–164 BR. Sica A (2004) Tumour-associated Yuan LJ. 131:309–323 regulated myeloid-derived suppressor cell contributes to hepato. 134. Asagiri M. Nat Rev stasis. Fang HY. Meng Taylor WR. Karin M (2004) The two NF-kappaB activation gene expression in cancer therapy. Coffelt SB. Majlessi L. Starr BA. Perez-Castro C. Shojaei F. Weidemann A. Aubry MC. Guma M. Zimmer cellular carcinoma development by impairing dendritic cell MA. Schreiber H (1995) Reichner JS (2005) Macrophage arginase regulation by CCAAT/ Inhibition of tumor growth by elimination of granulocytes. Kobayashi T. Kowanetz M. zation and angiogenesis mediate tumor refractoriness to anti- antitrypsin and neutrophil elastase imbalance and lung cancer VEGF therapy in mouse models. Lu KV. Nat Rev Immunol 9:609–617 cell-dependent tumour angiogenesis. Holsboer F. Am J Pathol Med 201:105–115 163:2221–2232 136. Am sword of immunity. Toledano AY. Du R. Mizukami Y. sion. Karin M. Rickman B. Cancer Lett 113. Cell 127. Song H. Deschamps C. Nature 453:807–811 alpha suppresses T-cell function and promotes tumor progres- 126. Mori Y. Capla JM. {alpha} isoforms in macrophages are essential for NO homeo- containing adaptors in Toll-like receptor signalling. Krowka MJ. Patel SA. Chest 128:445–452 106:6742–6747 117. Wesche DE. Greten VEGF treatment is mediated by CD11b + Gr1+ myeloid cells. Blood 114:844–859 D. Johnson RS. Li J. Doedens AL.Role of Tumour-Associated Myeloid Cells (TAMCs) 147 109. Simon MC (2010) macrophages as a prototypic type II polarised phagocyte Hypoxia-inducible factor 2alpha regulates macrophage function population: role in tumour progression. Chung DC (2005) Induction of interleukin-8 preserves the . N. Sobolewski A. Kohgo Y. Nizet V. FR. Gregory AD. Duerr EM. 131. Allavena P. Sica A. a small RWD-containing protein. Krieg AJ. van Bruggen N. Zhong C. Lynch MP. Marcussen N. AL. Murdoch C. Houghton AM (2011) Tumor-associated neutro. Une Y. Johnson neutrophils is required for acquisition of metastatic phenotype of N. Zinkernagel AS. Nature 441:431–436 (2010) Differential activation and antagonistic function of HIF- 123. Gala M. Lewis CE (2009) Hypoxia-inducible factors 1 and 2 Nat Biotechnol 25:911–920 are important transcriptional effectors in primary macrophages 110. Genes Dev 24:491–501 Immunol 7:353–364 140. Akassoglou K. Yao J. Karin M (2006) Nuclear factor-kappaB in cancer development Stockmann C. Swensen SJ. Simon MC. Gimotty PA. Gan J. Harris Fuh G. RSUME. Werb Z. Tepper OM. Penz-Oesterreicher M. Biswas SK. Wu X. Okada F. Karin M (2008) NF-kappaB DeNardo DG. Coussens LM. Hickey MM. Durham AC. Pekarek LA. J 120. Wu X. Sica A. Fredlund E. Chan DA. Shojaei F. Bowie AG (2007) The family of five: TIR-domain. 132. Daley JM. Kurt-Jones EA. Peyssonnaux C. Eur J Cancer 40:1660– in mouse models of acute and tumor inflammation. Musso T. Trends 435:323–345 Immunol 25:280–288 139. Bhagat G. Varesio L (2011) Hypoxia: a double-edged implications for tumor progression and anti-cancer therapies. Johnson RS (2009) Interdependence of hypoxic and Carano RA. Walmsley SR. Nizet V. Shojaei F. Yang P. Qu X. Paez-Pereda (2008) Overexpression of interleukin-1beta induces gastric M. Ganss R. Tu S. Tazawa H. Melillo G. Goldrath AW. Sun Z. innate immune responses. Ferrara N (2009) G-CSF-initiated myeloid cell mobili- Cunningham JM. Galiano RD. Morris SM Jr. 129. Mantovani A (2009) The yin-yang of tumor-associated neutro. O’Dea EL. Hughes R. Bjorkdahl O. Huang GJ (2011) Up. Simon MC. Peale FV. Keith B. Carbia-Nagashima A. Haddad GG. Passegue E. Liao D. Cowburn AS. Kulkarni AR. mediated by HIF-1alpha-dependent NF-kappaB activity. J Clin Invest 1667 120:2699–2714 125. (1995) A hypoxia-responsive element mediates a novel pathway phils: new targets for cancer therapy. Allavena P. Shock 23:168–172 Exp Med 181:435–440 137. Takeda N. Marks RS. 128. Imityaz HZ. 124. Hammond R. Locati M. Gurtner Immunity 31:761–771 GC (2004) Progenitor cell trafficking is regulated by hypoxic 114. Liang XH. Chilvers ER (2005) Hypoxia-induced neutrophil survival is benign murine fibrosarcoma cells: implication of inflammation. Cheng YR. Levine JP. Tan M. Malik AK. Mahoney EJ. Houghton AM (2010) The paradox of tumor-associated neutro. Farahi N. Exp Med 182:1683–1693 phils. Schanz S. Hu CE. Stalla GK. Johnson RS. Bonizzi G. J Clin Oncol 27:4709–4717 invasion. Turcotte S. Takaishi S. Jensen HK. Doedens A. Varesio L 119. enhances SUMO pressor cells in mice. Cancer Res of activation of the inducible nitric oxide synthase promoter. Cancer Cell 14:408–419 conjugation and stabilizes HIF-1alpha during hypoxia. Bergers G (2008) F. Rius J. RS (2010) Macrophage expression of hypoxia-inducible factor-1 scriptional regulation of HIF-1alpha. Albina JE. Williams EP. Cox GW. Cell 864 Cycle 9:1732–1737 133. Cancer Cell 13:206–220 116. YG. Nat Med 10:858– phils: fueling tumor growth with cytotoxic substances. 115. Rius J. Bastidas ways by bacteria promotes regulatory properties of neutrophils. Fox JG. Zhang X. Zhang RD. Bamlet WR. Wang TC 142. Yu L. Kim JW. Ferrara N (2007) Bv8 regulates myeloid. Proc Natl Acad Sci U S A risk. Methods Enzymol pathways and their role in innate and adaptive immunity. Cancer Cell 16:173–174 138. Blanchard experiencing hypoxia. Nature 450:825–831 130. Zukerberg LR. de Andrade M (2005) Alpha1. Wieben ED. gradients through HIF-1 induction of SDF-1. Baldwin ME. Imtiyaz HZ. Ceradini DJ. Tan M. Leclerc C. Arzt E (2007) inflammation and cancer and mobilizes myeloid-derived sup. Condliffe AM. Lewis C. Stockmann C. Lundbeck Vandenberg S. Jo WS. Deriaud E. Hosokawa M (2003) Infiltration of Cramer T. Hoffmann A. Cassatella MA. J Exp associated carcinogenesis and tumor progression. 122. Zhang N. 141.

Mantovani A. Mazzoleni S. Int J Exp Pathol 90:222– Van Ginderachter JA. Ryffel B. Quaglino E. Boccadoro M. Yang C. 231 Welsh L. Gabrilovich D. Pardoll D. Mazzieri R. Kortylewski M. angiogenic response in HIF-1alpha-deficient colon cancer cells. De Palma M. Falini Huang E. Jove R. Kim YS. Zonari E. Mol Med 14:2803–2815 Jove R. Swiderski P. Wang L. Mira JP. Kaiser LR. Catala L. Heller R. Venneri MA. Deng J. distribution. Finlayson E. Niu G. nates immature myeloid cells from tumor-bearing mice and Bourhis J. 65:3437–3446 Kujawski M. de . Lipton A (2010) Antitumor effects and anticancer inflammatory monocytes with immunosuppressive activity on applications of bisphosphonates. Phillipson 169. Nat Biotechnol 27:925–932 162. Signorelli M. 158. J Immunol conjugation to a TLR9 agonist enhances antitumor immune 165:6015–6019 responses. Zhang S. Sangaletti S. Niu G. Cancer Res 66:9299– Schlemmer F. angiogenesis and tumor growth in a human melanoma xenograft. Zou W (2009) Phenotype. Reisfeld 167. Fishman M. Cancer Cell 14:299– in the human tumor environments. Genin P. metastasis by inducing macrophage polarization and vessel Marchesi F. Amigorena S. Descamps P. Kang CY (2007) A combination of chemo- Activation of the NLRP3 inflammasome in dendritic cells immunotherapies can efficiently break self-tolerance and induce induces IL-1beta-dependent adaptive immunity against tumors. Hebbar M. Pardoll DM. antitumor immunity in a tolerogenic murine tumor model. Massaia M (2010) Zoledronic acid 11:1314–1321 repolarizes tumour-associated macrophages and inhibits mam- 148. Tugues S. Coppola D. Albelda SM RA. Delneste Y. Ghiringhelli F. Guiducci C. Lidereau R. Grusby MJ. Galli R. Liu Y. Cancer Res 63:4441– (2007) Toll-like receptor 4-dependent contribution of the 4449 immune system to anticancer chemotherapy and radiotherapy. Vogl T. Coscia M. Vinckier interleukin-1 blockade? Cancer Metastasis Rev 29:317–329 S. Smyth MJ. Mordoh J. Murdoch C (2009) Neutrophils: key M. Riganti Yu H (2005) Inhibiting Stat3 signaling in the hematopoietic C. Blanchard S. Fricke I. Bronte V (2006) Tumors induce a subset of 157. expressed in phagocytes: a novel group of damage-associated Vecchi A. Gallina G. interferon-alpha delivery by Tie2-expressing monocytes generation. Zitvogel L (2009) Sakaguchi S. Roth J (2007) S100 proteins 156. Suzuki E. Larsson E. De Palma M. Forman S. 161. Semin Oncol 37(Suppl 2):S30– CD8+ T cells. Jeannin P (2009) lymphoma by expanding regulatory T cells. Morgan G. 159. van Rooijen N. Saulnier P. Gabrilovich D (2003) All-trans-retinoic acid elimi- Nogues C. mary carcinogenesis by targeting the mevalonate pathway. Colombo MP adaptive immune responses by Stat-3 signaling in tumor cells. Ponsoda S. Ortiz C. Bravo AI. Pucci F. Yu B. Lush R. Ma Y. Knevels E. De Mol M. Joulin V. Jassar AS. Dewerchin M. Wittkowski H. Borrello I (2008) Myeloid. De Santo C. associated macrophages. Politi LS. J Cell Bhattacharya R. Bonardi C. 165. Simeone D. Kroemer G. Scuto A. Guidotti LG. and enhances antitumor immune activity. Bianchi G. Laoui D. A. Tasdemir E. Pardoll D. Kim YJ. Chang WS. Moi D. Noonan K. Pikarsky E (2005) Inflammation 163. Pantaleoni F. Wei S. J Leukoc Biol 81:28–37 tumor-associated macrophages and inhibition of MCP-1 reduce 145. Guglielmotti A. Blood 114:1141–1149 311 151. Markowitz D. Foell D. Forni G. Duluc D. Sotomayor E. Brombacher F. Himmelreich U. McLaughlin 166. Antonia S. 9307 Kanellopoulos J. Salomaki H. Neuger AM. Zanovello P. Kast WM and cancer: is the link as simple as we think? J Invest Dermatol (2001) Mechanism of immune dysfunction in cancer medi- 124:x–xiv ated by immature Gr-1+ myeloid cells. Yu H (2004) Regulation of the innate and 160. Dinarello CA (2010) Why not treat human cancer with C. Haynes NM. Invest Dermatol 127:2031–2041 Bicciato S. Chang SY. Welling TH. Barrat FJ. Velders MP. Int J Cancer 125:367–373 Thomas S. Lewis CE. Jove R. Yu H edge: STAT6-deficient mice have enhanced tumor immunity to (2009) In vivo delivery of siRNA to immune cells by primary and metastatic mammary carcinoma. Kujawski M. Johansson I. mediators of tumour angiogenesis. Criollo 5406 A. and functional and clinical relevance of Th17 cells inhibits tumor growth and metastasis. Maiuri MC. Serafini P. Lee H. Clin Cancer Res other 57:507–515 11:6713–6721 155. Segura I. Allavena P. Panaretakis T. Obeid M. Zhou H. Rolny C. Soifer HS. Gazzaniga S. Pilon. Aymeric L. Ortiz C. Botling J. Lissoni A. Carmeliet P (2011) HRG inhibits tumor growth and 170. Herrmann A. Mirza N. Kapoor V. Vicari AP. Garbi A. Curcio C. Chang A. Apetoh L. Delaloge S. derived suppressor cells promote cross-tolerance in B-cell Gamelin E. Maschi F. Tursz T. Naldini L (2008) Tumor-targeted Coukos G. Sica et al. Cheng P. Basso G. Cheng F. Zitvogel L improves the effect of vaccination. Dalton W. Cavallo F. J Immunol 166:5398– 152. Monkkonen H. Levi F. Dolcetti L. Buysschaert I. immune response in cancer patients. Ullrich E. Civas A. Claesson.148 A. Musiani P. Nat Med 15:1170–1178 Cancer Res 67:7477–7486 154. Vatan L. Ben-Neriah Y. Wang T. Borrello I. Squadrito ML. Kortylewski M. Kroemer G. Ryffel B. Wainstok R (2007) Targeting molecular pattern molecules. Frost Nat Med 13:1050–1059 TJ. Sotomayor EM. Nefedova Y. Kortylewski M. NM. Rossi JJ. normalization through downregulation of PlGF. Cancer Immunol Immun. Wei S. Ullrich E. 164. Nickoloff BJ. Gabrilovich DI. J Colombo MP. Ostrand-Rosenberg S. Mignot G. Erba E. Olimpio CO. Serafini P. Cancer Res 149. Liu R. Li X. Marigo I. Indraccolo S. Cheng T. Costa S. Xiang R. Nat Med Bosia A. Banerjee M. Iezzi M. Trinchieri G. Burdelya L. system elicits multicomponent antitumor immunity. Mgebroff S. Kerr WG. Holen I. (2005) Redirecting in vivo elicited tumor infiltrating macro- Nat Med 10:48–54 phages and dendritic cells towards tumor rejection. Andre F. Ko SY. retinoic acid improves differentiation of myeloid cells and Vermaelen K. Apetoh L. Akerud P. Uhl M. G. Kusmartsev S. Coulon 168. Szeliga W. Yang H. Tesniere A. Chompret A. Tazzyman S. Cancer Cell Nat Med 11:992–997 19:31–44 144. Lidereau R. Kay H. Luo Y (2008) A Legumain-based minigene (2005) Gemcitabine selectively eliminates splenic Gr-1+/ vaccine targets the tumor stroma and suppresses breast CD11b + myeloid suppressor cells in tumor-bearing animals cancer growth and angiogenesis. Tschopp J. Andre F. Ko HJ. Ghiringhelli F. Zhang S. Clavel-Chapelon F. Saftig P. Wang T. Kryczek I. Mazzone M. Hu HD. Sitia 150. Cancer Res Interferon-gamma reverses the immunosuppressive and protu- 68:5439–5449 moral properties and prevents the generation of human tumor- 147. Wyns S. Mule J. Dresselaer T. Gabrilovich DI (2006) All-trans- 153. Corvaisier M. Mignot G. Dunn M. Tesniere A. Shain K. Perfettini JL. J Clin Invest 116:2777–2790 S40 146. Chieppa M. Lush RM. Clements VK (2000) Cutting Raubitschek A. Lewen S. Kowolik C.

Neoplasia 10:329–340 tion. immune responses differentially regulate cancer development. Lewis CE. Chen YY. Nozawa H. Cancer Res 65:2964–2971 172. Jimeno J. D’Incalci M (2005) Anti-inflammatory tumor-promoting inflammation: impairment of macrophage properties of the novel antitumor agent yondelis (trabectedin): recruitment evokes a compensatory neutrophil response. Denardo DG. Erez N. Johansson M. Coussens LM (2008) Polarized 171. Tazzyman S. Murdoch C. inhibition of macrophage differentiation and cytokine produc.Role of Tumour-Associated Myeloid Cells (TAMCs) 149 Braud F. Hanahan D (2008) Plasticity in Immunol Rev 222:145–154 . Pahler JC.