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Reviewa maladaptive response that instead helps drive tumorgrowth through promotion of angiogenic programs, tissueremodeling, ectopic survival of malignant cells, and devel-opment of immunosuppressive microenvironments thatblunt cytotoxic T cell activities [10]. More recently, ithas been demonstrated that polarization of macrophagestowards tumor-promoting phenotypes is not exclusivelythe result of thwarted tissue homeostasis, but instead amore active process driven by what are probably reciprocalinteractions with both malignant and stromal cells in thelocal microenvironment [10,11]. Thus, in addition to dis-cussing well-accepted functions for tumor-associatedmacrophages (TAMs; Box 1), this review also focuses on

productionofvascular endothelialgrowth factor A (VEGFA),because overexpression of VEGFA partially reverses theeffects of macrophage depletion [36], and macrophage-spe-cific loss of VEGFA results in vascular normalization [37]. Insome tumor models, production of matrix metalloproteinase(MMP)-9 by TAMs mediates VEGFA bioavailability, thusprovidingan alternative, but stillVEGF-dependentroute forpromoting angiogenesis [38,39]. Similarly, the TAM produc-tion of placental growth factor (PIGF), a homolog of VEGFAthat selectively binds VEGF receptor 1 (VEGFR1), alsostimulates angiogenesis in tumors [40] and may in partexplain resistance to VEGFA and VEGFR targeted thera-pies in the clinic [4143]. Several other factors produced bymacrophages are also known to regulate vascular program-ming [4446], but their roles in tumorigenesis are not firmlyestablished and therefore are not discussed herein.

Recently a novel subset of macrophages expressingTie2, a receptor for angiopoeitins (ANGs) was described

Corresponding author: Coussens, L.M. (coussenl@ohsu.edu)* Current address: Department of Cell and Developmental Biology, Knight Cancer

Institute, Oregon Health and Sciences University, Rm 5508, Richard Jones Hall, 3181SW Sam Jackson Rd, Portland OR 97239-3098, USA.Differential macropin the tumor microBrian Ruffell1, Nesrine I. Affara1 and Lisa 1Department of Pathology, University of California, San Francis2Helen Diller Family Comprehensive Cancer Center, University San Francisco, CA 94143, USA

Of the multiple unique stromal cell types common tosolid tumors, tumor-associated macrophages (TAMs)are significant for fostering tumor progression. The pro-tumor properties of TAMs derive from regulation ofangiogenic programming, production of soluble media-tors that support proliferation, survival and invasion ofmalignant cells, and direct and indirect suppression ofcytotoxic T cell activity. These varied activities are de-pendent on the polarization state of TAMs that is regu-lated in part by local concentrations of cytokines andchemokines, as well as varied interactions of TAMs withnormal and degraded components of the extracellularmatrix. Targeting molecular pathways regulating TAMpolarization holds great promise for anticancer therapy.

Macrophages in solid malignanciesMacrophages are important residents of all tissues, wherethey play crucial roles in regulating tissue homeostasis. Inthis context, tissue-resident macrophages assist with com-bating infection [1,2], resolving acute inflammation [3],and in regulating metabolic response to tissue stress[4,5]. This broad range of functions, and the accompanyingplasticity required to permit such adaptive responses, alsoimplicates macrophages in several chronic pathologicalconditions including diabetes and atherosclerosis [57].Solid tumors represent an extreme example of a dysregu-lated tissue, and multiple characteristics of tumors, includ-ing hypoxia [8] and abundant cell death [9], help directmacrophage function towards attempting homeostatic res-toration. In the context of a tumor however, this represents1471-4906/$ see front matter 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.it.2011.12age programmingnvironment. Coussens1,2*

513 Parnassus Ave, HSW450C, San Francisco, CA 94143, USACalifornia, San Francisco, 513 Parnassus Ave, HSW450C,

recently recognized molecular and cellular mechanismsunderlying TAM polarization within tumor microenviron-ments, and the therapeutic implications of these findings.

TAM functionWith the exception of non-small cell lung carcinoma[12,13], patient prognosis in solid tumors is generallydescribed as correlating inversely with TAM density andexpression signatures [10,14]. TAMs have also been relat-ed to particular functional roles in human tumors, with anestablished association between TAM presence and densi-ty of tumor vasculature in several carcinomas [1518]including breast [1924], as well as increased local inva-sion and/or metastasis in melanoma [25], breast [26,27],ovarian [15,28], colorectal [29,30], pancreatic neuroendo-crine [31] and bladder [32] cancer. Less established inhumans is a role for TAMs in local immune suppression,although there have been several reports in ovarian cancer[3335]. A potential caveat of these studies is that most relyon immunohistochemical detection of CD68 for measure-ment of TAM density. However, CD68 is not a specificmarker of macrophages and is expressed by other stromalpopulations (Box 1), including those that may have over-lapping function with TAMs (Box 2).

AngiogenesisExperimental studies using murine carcinoma models haveclearly demonstrated that TAMs regulate vascular pro-gramming of tumors. Important for this activity is TAM.001 Trends in Immunology, March 2012, Vol. 33, No. 3 119

Box 1. Identity crisis

As their name implies, TAMs are found within or proximal toprimary tumors, and represent a mature population of terminallydifferentiated myeloid-lineage cells [55]. This location distinguishesthem from metastasis-associated macrophages [128], and they arephenotypically distinct from the heterogeneous population ofimmature myeloid cells that predominantly accumulate in theperiphery of tumor-bearing individuals, and are associated withimmune suppression [80]. Identifying TAMs can be difficult how-ever, as there are no lineage-defining markers for macrophages[128], and marker expression can vary by activation status andtissue localization [129]. In general, both human and mouse TAMscan be identified via flow cytometry through high surface expres-sion of CD11b, CD14 and MHCII/HLA-DR, in addition to the commonleukocyte antigen CD45. High expression of MHCII differentiates

ReviewTAMs from immature myeloid cells, as does low expression of Ly6Cin mice and CD34 in humans [128]. Murine TAMs are also commonlyidentified by expression of F4/80, an EGF-transmembrane 7 familymolecule of unknown function. However, not all macrophagepopulations express F4/80, and it has been observed on Langerhanscells in the skin and on eosinophils in adipose tissue. Dendritic cellsalso express MHCII, and subsets express CD11b and CD14, whereasthe most commonly used marker for dendritic cells, CD11c, isexpressed constitutively by certain tissue macrophages and inducedby inflammatory conditions such as those found in the tumormicroenvironment. The problem of accurately identifying TAMs ismore acute in humans because studies rely almost exclusively onsingle maker detection of CD68 via immunohistochemistry. Inaddition to other leukocyte populations, CD68 is expressed byfibroblasts, and at least for breast cancer is not a specific marker forTAMs [99]. Thus, although human studies are referenced here, thefunctions ascribed to TAMs based on correlations between TAMdensity and clinical parameters require validation in some tissues.[47]. Tie2+ TAMs tend to be closely associated withtumor vasculature, and have been found to be crucialfor angiogenesis in orthotopic [47] and transgenic tumormodels [48]. This activity depends in part on endothelialcell-produced ANG2 and the Tie2 receptor that directlocalization of Tie-2-expressing cells along the vasculature[48]. Notably, antagonists that block ANG2 restrict tumorgrowth in mouse models of de novo mammary carcinogen-esis, that is, MMTV-PyMT mice [49], a property thathas thus far not been observed in tumors following block-ade of TAM infiltration [50], or by myeloid-specificVegfa ablation [37], thus hinting at a unique mode ofaction either downstream or parallel to VEGFA bioactivi-ty [48].

Box 2. Tumor commune

Although TAMs may constitute the majority of immune cells insome tumors, additional myeloid and mesenchyme-derived cellspervade tumors and are known to overlap functionally with TAMs.This includes granulocytic mast cells, neutrophils and immaturemyeloid cells that can be angiogenic, immunosuppressive, andpromote metastasis through pathways akin to those employed byTAMs [128]. Cancer-associated fibroblasts have also been shown topromote vascularization through SDF-1 [130] and IL-1b [131],whereas mesenchymal stem cells promote metastasis throughCCL5 [132] and are potentially immunosuppressive [133]. Mono-cyte-derived cells with a fibroblast morphology, or fibrocytes, areincreased during chronic inflammation, and based upon their dualmacrophage/fibroblast phenotype [70] are probably an emergingcell population involved in tumorigenesis.

120Invasion and metastasisThe most comprehensively described mechanism throughwhich TAMs promote solid tumor development is by pro-viding factors that enhance invasion of malignant cells intoectopic tissue. This activity centers around a paracrineinteraction loop involving macrophage-expressed epider-mal growth factor (EGF) and epithelial cell-expressedcolony-stimulating factor (CSF)1, also known as macro-phage CSF [51]. Increased expression of CSF1 is a signifi-cant mechanism underlying macrophage recruitment intotissues [50,5254] after CSF1 binding to its high affinityreceptor (CSF1R) expressed on resident macrophages andsome macrophage precursors. This interaction promotesmacrophage proliferation, survival and tissue recruitmentduring development (e.g. branching morphogenesis in themammary gland) [55], homeostasis [56], and pathologicaltissue remodeling processes such as those associated withacute tissue injury [53,5759] and during solid tumordevelopment [50]. Chemokines such as CC ligand(CCL)2 and stromal-derived factor-1 (SDF-1; CXCL12)are also important for TAM recruitment with demonstrat-ed roles in models of glioblastoma, melanoma, and cervicaland prostate cancer [38,39,6065]. Crucially, in addition tosupporting TAM recruitment, activation of intracellularsignaling pathways downstream of the CSF1CSF1R in-teraction significantly enhances EGF expression, which inturn regulates epithelial cell migration in some tissues[51,6668].

Macrophages also regulate composition and structure ofextracellular matrix (ECM) through their deposition ofECM components, for example, various types of collagens,and breakdown of these same components via their releaseof MMPs, serine proteases and cathepsins [6971]. Migra-tion on and through ECM is a necessary aspect of cellmigration [72], and thus by extension, TAMs are thought toregulate tumor and stromal cell migration/invasionthrough ECM. This activity has been directly demonstrat-ed in vitro [73,74] and in vivo with mice genetically defi-cient for cathepsin B, cathepsin S and urokinase/plasminogen activator (uPA), all of which derive primarilyfrom TAMs in the tumor microenvironment [7577]. MMP-dependent cleavage of the ECM [69], collagen deposition[78], and alteration of collagen structure [79] are alsopotential sources of regulation mediated by TAMs, butformal demonstration of these is lacking.

Immune suppressionSolid tumors are well recognized for repressing the activityof cytotoxic T cells, and are thus characterized grossly asimmunosuppressive. Although regulatory T (Treg) cellshave garnered much attention owing to this capability,recent literature also recognizes macrophages as majordeterminants of immune suppression in solid tumors. Al-though the mechanisms underlying these activities are lesswell characterized as compared to myeloid-derived suppres-sor cells, for example [80], TAMs do typically express severalgenes with immunosuppressive potential [68,81,82], andare capable of directly limiting T cell proliferation during

Trends in Immunology March 2012, Vol. 33, No. 3classic in vitro suppressive assays [8,34,50,83]. TAMs alsoact through intermediates to regulate immune suppression,as has been reported for recruitment of Treg cells by CCL22

[33], and may be important mediators of T cell recruitmentbased upon the inverse correlation between the presence ofCD68+ TAMs and CD8+ T cells in human breast cancer, andthe enhanced CD8+ T cell infiltration observed during che-motherapy in the MMTV-PyMT model following blockade ofthe CSF1CSF1R pathway [50].

In murine tumor models, suppression of CD8+ T cellproliferation by TAMs is at least partly dependent on me-tabolism of L-arginine via arginase-1 or inducible nitricoxide synthase (iNOS) [8,83], and resulting production ofoxygen radicals or nitrogen species [84,85]. By contrast,suppression of CD8+ T cells by human TAMs can occurindependent of L-arginine metabolism [34], and insteadmay rely on the B7 family of molecules as has been describedfor B7-H1 (programmed cell death 1 ligand 1; PD-L1) inhepatocellular carcinoma [86], and B7-H4 in ovarian cancer[34]. This distinction may be a result of differences between

human and murine macrophages, as expression of Arginase-1 by the former does not correlate with macrophage polari-zation. Alternatively, the tissue-specific microenvironmentcould dictate the mechanism of TAM suppression. As anexample of this, it has been described that ovarian TAMs areexposed to minimal levels of interleukin (IL)-4, which inother circumstances may downregulate B7-H4 expression[34]. TAMs from murine mammary and human breastcarcinomas however are exposed to significantly higheramounts of IL-4/13 [68,87], and thus one would anticipateminimal expression of B7-H4 in TAMs from these tissues.

Mechanisms of TAM polarizationThe description of macrophage activation as either classi-cal [M1; interferon (IFN)g/lipopolysaccharide (LPS)-de-pendent] or alternative (M2; IL-4/IL-13/IL-10/FcgR-dependent) has provided a necessary framework for the

MacrophageEndothelial cell

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oph

Hypoxic Invasive

eliapoxcleu

F4/80LectinHypoxiaDAPI

ayed

Review Trends in Immunology March 2012, Vol. 33, No. 3Macr

Perivascular

EndothHyNu

Figure 1. TAM localization within unique tumor microenvironments. Centrally displa late-stage tumor from the MMTV-PyMT mouse model of mammary carcinogenesis.

vasculature as revealed by perfusion with tomato lectin (green) and DAPI nuclear stain (

TAMs within a hypoxic region, at a locally invasive edge, in a normoxic area within thage

Intratumoral

l cellias

TRENDS in Immunology

is an immunofluorescent confocal micrograph of F4/80+ macrophages (red) withinAlso shown are areas of hypoxia detected with pimonidazole (yellow), functional

blue). Clockwise from top left, insets display enlarged graphical representations of

e tumor, and associated with the vasculature.

121

understanding of TAM polarization [88]. However, eventhough the M1/M2 designations represent extreme ends ofa scale, the concept is an oversimplification of the diversityof TAM phenotypes evident simply based on their locali-zation within tumors (Figure 1). TAMs do not becomepolarized by virtue of their location per se, but insteadreceive signals from the particular microenvironment inwhich they reside (Figure 2). These heterotypic signalsmay overlap, for example, IL-4 promotes both Egf andArginase-1 expression by TAMs [68], whereas other signalsmay be unique to particular microenvironments, such ashypoxic zones within solid tumors that also induce Argi-nase-1 expression [8], but which are not found along vas-culature where invasive macrophages are localized. Fromthese two examples, all murine TAMs would be anticipatedto express higher levels of arginase-1 than normal tissuemacrophages, but the suppressive capabilities of intratu-moral TAMs in hypoxic regions would be even further

enhanced. Thus, in addition to differentiation of TAMs,from either Tie2+ [89] or other monocyte precursors [83]that may preferentially home to specific localizations, onecan envision that integration of these distinct signalsresult in production of an array of TAM populations/phe-notypes with unique tumor-regulating properties [10]. It isimportant to note that the composition of the immunemicroenvironment [68,90,91] and the overall polarizationstate of TAMs becomes more favorable towards growthduring tumor progression [92]. The functional role ofmacrophages during tumor initiation [93,94] thereforediffers from that during tumor progression.

Immune microenvironmentConsistent with the original description of alternativeactivation, the type 2 cytokine IL-4 [68,77], and immuno-globulin (Ig) signaling through activating types of Fcgreceptors [91], exert significant regulation on TAMs in

(d)

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Figure 2. TAMs as central regulators of the tumor microenvironment. Factors that pr

into those derived from the immune system, actively produced by tumor cells, or re

factors such as immune complexes. (b) Neoplastic cells can produce chemokines th

well as directly producing immunosuppressive molecules such as IL-10 and PGE2. (c

cell death. These signals all direct the protumor functions of TAMs (df) including im

suppression can occur through soluble or cell surface mediators, and may be indireectopic tissue can be promoted through directed release of cytokines such as EGF, or

migration or increase chemoattractant bioavailability. (f) In addition to the interplay of

factors, subsets of TAMs expressing the Tie2 receptor interact with mural cells/pericyte

122PIGF

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te the polarization of TAMs towards a protumor phenotype (ac) can be subdivided

ng from tissue stress. (a) From leukocytes, this includes cytokines and other soluble

cruit macrophages, including CSF1 and CCL2, depending on the tissue involved, as

ns of dysregulated tissues include leaky vasculature, hypoxia, ECM remodeling and

e suppression, tumor cell dissemination, and promoting angiogenesis. (d) Immune

uch as through the recruitment of regulatory T cells. (e) Neoplastic cell invasion of through protease-dependent ECM remodeling that may directly affect neoplastic

TAMs with endothelial cells through production of VEGFA and other angiogenic

s to regulate vascular structure.

their ability to direct TAM protumor phenotype. IL-13derived from malignant epithelial cells or TH2-polarizedCD4+ T cells [87], or CD1d-restricted natural killer T(NKT) cells [95], may have similar effects on TAM polariza-tion due to overlapping IL-13 and IL-4 signaling cascadesthat lead to signal transducer and activator of transcription(STAT)6 activation, but this has yet to be proven in vivo.Likewise, activation of STAT3 by IL-10 suppresses IL-12[96] and tumor necrosis factor-a (TNF-a) expression [97] byTAMs, but the source of IL-10 and the relevance of thispathway to tumor development is unclear. Intriguingly,although IL-4 from TH2-polarized CD4

+ T cells is necessaryfor TAM programming in the MMTV-PyMT mammarycarcinoma model for EGF expression and promotion ofmetastasis, the absence of Igs in B-cell-deficient mice doesnot affect tumorigenesis [68]. Conversely, autoantibodies inthe K14-HPV16 mouse model of squamous carcinogenesisdrive TAM-dependent angiogenesis by FcRg-dependentmechanisms [91], whereas animals deficient in CD4+ T cellshave only mildly reduced tumor incidence [98]. These para-doxical findings probably indicate tissue-specific dependen-cies in each respective tumor model, and argue for detailedanalysis of counterpart human tissue as a precursor toclinical translation because human tumors could vary con-siderably in leukocyte composition.

Such human/mouse differences have been described inbreast/mammary cancer. Notably, leukocyte composition inmurine mammary carcinomas is dominated by TAMs,whereas lymphocytic infiltrate, predominately CD4+T cells,comprises the majority of immune cells in human breastcarcinomas [68,99]. CD4+T cells from human breast cancersexpress high levels of IFNg, resulting in protein concentra-tions >10-fold higher than IL-4 or IL-13 in human tumors[87]. This suggests divergent cytokine milieus betweenhuman and mouse tissue, because tumor CD4+ T cells fromMMTV-PyMT-derived mammary tumors exhibit high ex-pression of IL-4, IL-13 and IL-10, but produce minimal IFNg[68]. Given the strong polarizing effects of these cytokines,and the potential for synergistic effects on macrophagephenotype [100], transcriptional profiling of purified humanTAMs should prove informative in relating functional datain mouse models to correlative studies in patients.

Tumor-derived mediatorsIn addition to its potential production by multiple leuko-cyte subsets, IL-10 is secreted in vitro by many humancarcinoma cell lines [101], which in some instances actuallyreflects its origin in vivo [102]. Well established as a broadimmunosuppressive molecule, in vitro administration ofIL-10 to macrophages inhibits production of proinflamma-tory cytokines and chemokines [103], and reduces surfaceexpression of major histocompatibility complex (MHC)II,and the co-stimulatory molecules CD80 and CD86 [104].IL-10 also synergizes with IL-4 to induce Arginase-1 ex-pression in macrophages, possibly through induction of IL-4 receptor a [103]. As mentioned however, the source of IL-10 in tumor microenvironments is unclear, and may evenderive from TAMs themselves [96,97,105]. Interestingly,

Reviewthe ability of TAMs to produce IL-10 has been associatedwith another molecule produced by tumor cells, prosta-glandin E2 (PGE2), suggesting that this may also regulateTAM polarization [97,106] through prostaglandin (EP) 2and EP4 receptors [107]. The importance of PGE2 in canceris inferred from the preventative effects of cyclooxygenase-2 (COX-2) inhibitors including aspirin in colon [108,109]and respective transgenic mouse models [108], as well as aless prominent effect in several other cancers [110]. In theAPCMin/+ mouse model of intestinal tumorigenesis, COX-2inhibition reduces expression of Arginase-1 and increasesthat of CXCL1 [111]; both changes that are also associatedwith repolarization of TAMs. Whether this repolarizationis important for therapeutic efficacy of COX-2 inhibitors isunknown however, because PGE2 has pleiotropic effects onmultiple aspects of tumor development [108].

Homeostatic imbalanceHypoxic conditions exist within solid tumors in areasdistal from functional vasculature (Figure 1). Althoughnutrient deprivation is the goal of antiangiogenic therapy,the resulting hypoxia actually seems to promote malig-nant conversion and metastasis [112]. This response tooxygen availability is mediated primarily through hypox-ia-inducible factor (HIF)-1a and HIF-2a; both of whichalso regulate macrophage function [113]. Using LysM-cremice to induce myeloid-specific loss of either HIF-1a orHIF-2a, two recent reports have established that theprotumor functions of TAMs are likewise dependent onHIFs [8,114]. Loss of HIF-1a limited Arginase-1 expres-sion and the suppressive capabilities of TAMs in theMMTV-PyMT model [8], whereas loss of HIF-2a reducedTAM recruitment through lower chemokine receptor ex-pression in models of inflammatory hepatocellular andcolon carcinoma [114]. Despite the divergent mechanismsimplicated in each study, both observed reduced tumorvolume and progression, suggesting either tissue-specificroles for TAMs and/or involvement of overlapping path-ways regulated by HIF-1a or HIF-2a. This includes thepossible induction of an angiogenic response that was notthoroughly evaluated in either study, but which has beenassociated with TAMs localized to hypoxic regions oftumors [83,115]

The mislocalization of cellular and extracellular compo-nents is another prominent feature of tumors due to celldeath and dysregulated tissue architecture, respectively.The presence of extracellular ATP, high-mobility group box1 protein (HMGB1), and other normally intracellular mole-cules is detected by a class of receptors on the surface ofmacrophages called Toll-like receptors (TLRs) [6]. Al-though TLR signaling in dendritic cells is important forgenerating an adaptive immune response following cyto-toxic therapies through TLR4 recognition of HMGB1 [116],both TLR4 and TLR2 signaling promote growth of cell linesin the lung through induced TNF-a production by macro-phages [117,118]. For TLR2, this can be mediated bytumor-derived versican [118], but other ECM componentsincluding biglycan and hyaluronan also induce proinflam-matory cytokine expression by macrophages via TLR2 andTLR4 [119], and are potentially important in dictatingTAM polarization. Crucially, these ECM components do

Trends in Immunology March 2012, Vol. 33, No. 3not bind TLRs in their native form in noninflamed tissue,but become TLR ligands following degradation by proteasecleavage or interaction with reactive oxygen or nitrogen

123

species, thereby forming putative sensory pathways fordetection of inflammation and tissue disruption.

Concluding remarks: targets for therapyThe pathways that engage and mediate the maladaptiveresponse of TAMs present attractive therapeutic targets;several of which have already shown promise in the pre-clinical arena, and improve therapeutic responses to che-motherapy [37,50,120]. Therapeutic strategies directed atTAMs can be grouped crudely into four prospective themes:blocking effector function, limiting recruitment, repro-gramming, or preventing protumor polarization. Monoclo-nal antibodies and small molecular inhibitors targeting theVEGF and EGF pathways are already approved for treat-ment of various carcinomas alone or in combination, al-though none were designed specifically to target TAMfunction, and their clinical efficacy has been mixed[121,122]. It has recently been established that blockingTAM recruitment and/or survival in solids tumors (inmurine models) improves efficacy of cytotoxic therapies[50,123], in a manner dependent upon CD8+ T cells [50].Although monoclonal antibodies against CD11b have beenunsuccessful as single agents for the treatment of inflam-matory disorders, antagonists targeting the CSF1CSF1Rpathway in breast cancer and the CCL2CCR2 axis inprostate cancer are now in early phase clinical trials.

We anticipate emerging therapeutics to focus on repo-larization as a method to invoke the antitumor potential ofTAMs, as has been reported in pancreatic ductal adeno-carcinoma for agonist antibodies against the co-stimulato-ry molecule CD40 [120], and the use of Tie2+ monocytes todelivery IFNa to tumors [124]. Additional approachesinclude synthetic TLR ligands such as CpG [125] or imi-quimod [126], although reports that TLR signaling andnuclear factor (NF)-kB activation in TAMs promote tumorgrowth [117,118,127] suggest that TLR ligands must beused in a multitargeted approach [125]. Based upon ourfindings in mouse models of mammary and squamouscarcinogenesis, we are currently evaluating whether block-ing protumor polarization of TAMs, as opposed to directrepolarization, is similarly efficacious in preclinical modelsin combination with chemotherapy. Although this mayseem like a distinction without a difference, we hypothe-size that this approach may be less prone to refractoryresponses and adverse autoimmune side effects.

AcknowledgmentsThe authors thank Dr Anna Wasiuk for helpful discussion. This work wassupported by a Department of Defense Breast Cancer Research Program(BCRP) Fellowship to B.R., and grants from the NIH/NCI (R01CA130980,R01CA132566, R01CA140943, R01 CA155331), the Department ofDefense BCRP Era of Hope Scholar Expansion Award (W81XWH-10-BCRP-EOHS-EXP) and W81XWH-08-PRMRP-IIRA to L.M.C.

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Nat. Rev. Immunol. 8, 726736

Differential macrophage programming in the tumor microenvironmentMacrophages in solid malignanciesTAM functionAngiogenesisInvasion and metastasisImmune suppression

Mechanisms of TAM polarizationImmune microenvironmentTumor-derived mediatorsHomeostatic imbalance

Concluding remarks: targets for therapyAcknowledgmentsReferences