Cancer-promoting tumor-associated macrophages: New vistas and open questions

48 Coller, B. S., Arterioscler. Thromb. Vasc.

Biol. 2005. 25: 658–670.

Correspondence: Dr. Filip K. Swirski, Center

for Systems Biology, Massachusetts General

Hospital and Harvard Medical School,

Simches Research Building, 185 Cambridge

St., Boston, MA 02114, USA

Fax: 11-617-643-6133

e-mail: [email protected]

Additional Correspondence: Dr. Mikael J.

Pittet, Center for Systems Biology,

Massachusetts General Hospital and Harvard

Medical School, Simches Research Building,

185 Cambridge St., Boston, MA 02114, USA

Fax: 11-617-643-6133

e-mail: [email protected]

Received: 5/5/2011

Revised: 20/6/2011

Accepted: 1/8/2011

Key words: Atherosclerosis � Cancer �Monocyte

Abbreviations: LXRs: liver X receptors �MDSCs: myeloid-derived suppressor cells �

PPARs: peroxisome proliferator-activated

receptors � TAMs: tumor-associated macro-

phages

See accompanying Viewpoints:http://dx.doi.org/10.1002/eji.201141719http://dx.doi.org/10.1002/eji.201141894

The complete Macrophage Viewpoint

series is available at:http://onlinelibrary.wiley.comdoi/10.1002/eji.v41.9/issuetoc

Cancer-promoting tumor-associated macrophages: New vistas and open questions

Alberto Mantovani1, Giovanni Germano1, Federica Marchesi1, Marco Locatelli2

and Subhra K. Biswas3

1 Istituto Clinico Humanitas IRCCS and Dept. Translational Medicine, University of Milan, Rozzano, Italy2 Department of Neurosurgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of

Milan, Milano, Italy3 Singapore Immunology Network, Agency for Science, Technology and Research, Singapore DOI 10.1002/eji.201141894

Tumor-associated macrophages

(TAMs) are key components of the

tumor macroenvironment. Cancer-

and host cell-derived signals gener-

ally drive the functions of TAMs

towards an M2-like polarized, tumor-

propelling mode; however, when

appropriately re-educated. TAMs also

have the potential to elicit tumor

destructive reactions. Here, we

discuss recent advances regarding the

immunobiology of TAMs and high-

light open questions including the

mechanisms of their accumulation

(recruitment versus proliferation),

their diversity and how to best ther-

apeutically target these cells.

Introduction

It is estimated that about 25% of cancers

are linked to chronic inflammation

sustained by chronic infections (e.g.

inflammatory bowel disease, IBD) or

inflammatory conditions of diverse origin

(e.g. prostatitis) [1]. Moreover, inflam-

matory cells and mediators are also

present in the microenvironment of

virtually all tumors that are not epide-

miologically related to inflammation [1].

Two pathways link inflammation and

cancer. The first, the extrinsic pathway,

is driven by exogenous conditions which

cause non-resolving smouldering inflam-

matory responses; the second, the intrin-

sic pathway, is triggered by mutation of

either oncogenes or tumor suppressor

genes that activate the expression of

inflammation-related programmes [1].

Macrophages are a key component of

cancer-related inflammation (CRI) [1–4].

In many tumors, a correlation between

increased numbers and/or density of

macrophages and poor prognosis has

been observed [5–7]. The molecular

mechanisms underlying the cancer-

promoting activities of tumor-associated

macrophages (TAMs) include the promo-

tion of proliferation and survival of

malignant cells, the subversion of adap-

tive immune responses, and the promo-

tion of angiogenesis, stroma remodelling

and metastasis formation [1, 2]. More-

over, there is evidence strongly suggest-

ing that TAMs are critical determinants of

the tumor response to hormonal therapy

and chemotherapy [8–10].

Here, we will discuss recent advan-

ces that have shed new light onto the

immunobiology of TAMs and their

viability as therapeutic targets. In

particular, we will emphasize the open

questions and stumbling blocks to

diagnostic and therapeutic exploitation

building on previous reviews that

provide the framework for the present

contribution, which by virtue of being a

Viewpoint is restricted in length [1–4].

TAM accumulation

It has long been held that TAMs

originate from circulating monocytes

and that tumor-derived chemoattrac-

tants play a key role in monocyte

recruitment [11] (Fig. 1). Chemokines

(e.g. CCL2) have been known to be

associated with macrophage infiltration

in experimental and human tumors for

over 25 years (e.g. [12–16]). For

instance, gliomas are characterized by

the long recognized production of a

wide spectrum of chemokines, by the

expression of chemokine receptors and

by the correlations between chemokine

Eur. J. Immunol. 2011. 41: 2470–2525Macrophage Viewpoints2522

& 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

production/receptor expression and

clinical outcome; the chemokine reper-

toire of gliomas includes CCL2, CXCL8,

CXCL12, CXCL10, CCL3L1, CX3CL1

(e.g. [17–19]).

It has been assumed that chemokine-

driven entry of monocytes accounts for

the maintenance of TAM levels in a

growing tumor; however, physiologically,

mouse microglia cells relevant to gliomas

are self-sustained and do not depend on

continuous replenishment from the circu-

lation [20]. Moreover, in a mouse model

of type II inflammation using nematode

infection, local IL-4-dependent macro-

phage proliferation is shown to be a key

determinant of the numbers of M2-polar-

ized macrophages in the lung [21]. In the

same vein, a recent paper in this Journal

by Taylor and colleagues demonstrates

that macrophage accumulation in the

inflamed peritoneum depends on

macrophage proliferation [22]. Early

studies also showed in situ proliferation

of TAMs (e.g. [23–25]) (Fig. 1). For

instance, in a murine sarcoma, a para-

crine circuit involving M-CSF produced

by tumor cells and high levels of c-fms

production by TAMs was identified as a

mechanism of macrophage proliferation

and survival in situ [25]; however, M-

CSF is a relatively poor CSF in humans

and therefore it remains unclear whether

proliferation is a major determinant

sustaining human macrophage numbers

in tissues [26, 27], although proliferation

[28] has been detected in human

monocytes. Furthermore, macrophage

mitosis has rarely been observed in

specimens from human tumors, with the

exception of Kaposi’s sarcoma [11].

Given the old and new findings

discussed here, the issue of in situ

macrophage proliferation as a mechan-

ism contributing to TAM levels needs to

be re-examined using the current tech-

nology and focusing on human tumors,

particularly as this issue may have

important bearings on the development

of therapeutic strategies.

TAM diversity: Both location andcancer-type matter

Plasticity and diversity are hallmarks of

the mononuclear phagocyte system

[1–4, 29, 30] and there is now evidence

that TAMs in murine tumors consist of

cell populations with substantial differ-

ences [31]. In a transplanted mammary

carcinoma in normoxic and hypoxic

areas TAMs were reported to have an

M1-like and M2-like phenotype, respec-

tively [30]. The microanatomical distri-

butions of cells with different

phenotypes and their relation to mono-

cyte subsets [30] remain to be deter-

mined, however.

A further layer of diversity, namely

the diversity of mechanisms responsible

for TAM generation, occurs at the level

of the tumors and organs involved. Here

are some telling examples. In a model of

human papilloma virus-driven squa-

mous epithelium carcinogenesis, a

remote control pathway involving

CD41 T cells, B cells, antibodies and

Fcg receptors are responsible for the

M2-like phenotype of tumor-promoting

TAMs [32]. In contrast, in a mammary

carcinoma, Th2-derived IL-4 promotes

M2 polarization and metastasis [33]. In

a transplanted mammary carcinoma,

complement was shown to be involved

in myelomonocytic cell recruitment

[34], although the mechanisms

responsible for complement activation

in tumors remain to be defined. It

should be noted that B cells can use

tools other than antibodies to skew

macrophage function and promote

tumor progression, including IL-10 and

lymphotoxin (LT) [35–38], and B

regulatory cells may be well suited for

this [38]. Thus, the mechanisms of

co-opting the function of myelomono-

cytic cells in tumors can differ consid-

erably, although M2-like skewing is a

recurrent common denominator.

Treg cells are characterized by

expression of the Foxp3 transcription

factor. It has recently been observed

that a subset of mouse macrophages

express Foxp3 [39]. Foxp31 macro-

phages appear late in the B16 mela-

noma and, upon adoptive transfer,

promote tumor growth. It will be

important to confirm and extend these

observations to human TAMs.

The diversity of TAMs impacts on the

design of therapeutic strategies given

that, in different tissues and tumors, the

pathways orchestrating TAM develop-

ment and cancer-related inflammation

can differ considerably, and that

myelomonocytic cells come in different

Figure 1. Pathways responsible for macrophage commutation and skewing of macrophagefunction in the tumor microenvironment. The picture is a compound of data obtained indifferent tumors. Lymphoid cell-derived signals, including Th2 cells, Treg cells and B cells,influence the TAM phenotype. Moreover, tumor cells and stromal cells are a source of mediatorsinfluencing recruitment, proliferation and functional orientation of TAM.

Eur. J. Immunol. 2011. 41: 2470–2525 Macrophage Viewpoints FORUM 2523


flavours in different tumor contexts.

Nonetheless, mononuclear phagocytes

remain as essential common constitu-

ents of cancer-related inflammation and

determining their diversity in different

human cancers is a prerequisite to

translate recent progress in this field

into clinical benefit.

Therapeutic targeting

In most established malignant tumors

TAMs express an M2-like phenotype,

although there are variations and excep-

tions to this common theme [40]. The

TAM phenotype is reversible and these

cells can be re-educated to exert anti-

tumor activity [41–43]. In a recent study

[44], anti-CD40 antibodies with agonist

activity have been shown to have anti-

tumor potential in both murine and

human carcinoma of the pancreas.

Circumstantial evidence suggests that

the anti-tumor activity of CD40 agonist

antibodies is mediated by macrophage

activation. These recent [44] and

previous [4] results, including data from

patients suggest that it is indeed possible

to tip the macrophage balance in an anti-

tumor direction. [10].

Tumor-targeted monoclonal anti-

bodies are part of the cancer ther-

apeutic armamentarium. Macrophages

can mediate antibody-dependent cellu-

lar cytotoxicity and there is evidence

that M2-polarized macrophages phago-

cytose antibody-sensitized lymphoma

cells more efficiently than non-polarized

macrophages [45]. This observation

may explain the apparently divergent

prognostic significance of TAMs in

follicular lymphoma treated with

chemotherapy alone (unfavourable)

and with anti-CD20-containing regi-

mens (favourable) [46]. Thus, the

interaction of macrophages in different

states of activation with antibodies and

more generally with B cells is context-

dependent and can result in promotion

of carcinogenesis (e.g. [33, 35, 38, 47])

or anti-tumor activity [3].

Reducing the numbers or eliminat-

ing TAMs are alternatives to their

re-education. Strategies include inter-

ference with the M-CSF axis [13] or

chemokine expression/function (in

particular CCL2, e.g. [13, 15]), or

depletion of angiogenic monocyte

subsets [48, 49]. Moreover, the influ-

ence of selected chemotherapeutic

agents on the viability and function of

myelomonocytic cells may contribute to

or be a critical component of the agents’

anti-tumor activity [9, 50, 51]. Thus,

the current understanding of TAM

biology opens up different and alter-

native strategies to target these cells,

although the careful definition of the

immunobiology of the context in

different tumors, as noted in the

previous section, may be required for

successful therapeutic exploitation.

Concluding remarks

Macrophages can act as a double-edged

sword in cancer [4, 11]. It has long

been known that appropriately acti-

vated mononuclear phagocytes can

express anti-tumor activity in vitro and

in vivo by direct killing of tumor cells

and/or by eliciting vascular damage

and tissue destruction; however, in the

Darwinian evolution of tumors, TAMs

are co-opted as an integral component

of the neoplastic microenvironment.

Identification of the pathways respon-

sible for the skewing of macrophage

function raises the possibility of macro-

phage-targeted therapies, complemen-

tary to cytoreductive approaches, and of

exploiting TAM as prognostic indicators

[7]; however, a number of open ques-

tions remain as discussed, including the

role and mechanism of recruitment

versus in situ proliferation, and the

diversity both within the tumor micro-

environment and between different

tissues and tumors. A better under-

standing of these issues may help the

better exploitation of the diagnostic and

therapeutic potential of TAMs.

Acknowledgement: Alberto Mantovani issupported by Associazione Italiana per laRicerca sul Cancro, Special Project 5x1000.

Conflict of interest: The authors declare nofinancial or commercial conflict of interest.

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Correspondence: Prof. Alberto Mantovani

Istituto Clinico Humanitas IRCCS, University

of Milan, Via Manzoni 113, 20089 Rozzano,

Italy

Fax: 139-0-02-8224-5101

e-mail:

[email protected]

Received: 24/6/2011

Revised: 18/7/2011

Accepted: 20/7/2011

Key words: Cancer � Chemokines � Inflam-

mation � Macrophages � Tumor-associated

macrophages

Abbreviation: TAM: tumor-associated

macrophage

See accompanying Viewpoints:http://dx.doi.org/10.1002/eji.201141719http://dx.doi.org/10.1002/eji.201141727

The complete Macrophage Viewpointseries is available at:http://onlinelibrary.wiley.comdoi/10.1002/eji.v41.9/issuetoc

Eur. J. Immunol. 2011. 41: 2470–2525 Macrophage Viewpoints FORUM 2525


Cancer-promoting tumor-associated macrophages: New vistas and open questions

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