Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes

doi:10.1016/S1471-4906(02)02302-5

Trends in Immunology

Volume 23, Issue 11, 1 November 2002, Pages 549-555

https://doi.org/10.1016/S1471-4906(02)02302-5 Get rights and content

Abstract

Mononuclear phagocytes are versatile cells that can express different functional programs in response to microenvironmental signals. Fully polarized M1 and M2 (or alternatively activated) macrophages are the extremes of a continuum of functional states. Macrophages that infiltrate tumor tissues are driven by tumor-derived and T cell-derived cytokines to acquire a polarized M2 phenotype. These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.

Section snippets

Properties of polarized M1 and M2 macrophages

Macrophage activation in response to microbial agents and cytokines, interferon-γ (IFN-γ) in particular, has long been recognized [6]. More recently, it was realized that anti-inflammatory molecules, such as glucocorticoid hormones, IL-4, IL-13 and IL-10, are more than simple inhibitors of macrophage activation, in that they induce a distinct activation program (alternatively activated macrophages) 1., 2..

Polarized macrophages differ in terms of receptor expression, effector function and

Recruitment

TAMs derive from circulating monocytic precursors and in situ proliferation is generally not an important mechanism that sustains the mononuclear phagocyte population, at least in human tumors [3]. Several lines of evidence, including correlation between production and infiltration in murine and human tumors, passive immunization and gene modification, indicate that chemokines have a pivotal role in the recruitment of monocytes in neoplastic tissues 3., 11.. Tumors are generally characterized

Links to adaptive immunity: the IL-10–TGF-β connection

TAMs have poor antigen presenting capacity and can suppress T-cell activation and proliferation by releasing prostaglandins, IL-10 and TGF-β 4., 32., 33., 34., 35., 36.. Moreover, they have an IL-10^high IL-12^low phenotype, characteristic of M2 cells. Autocrine IL-10 accounts, in part, for defective IL-12 production [32].

Ibe et al. have recently suggested that during tumor establishment, T cells condition TAMs to produce IL-10 and that inactivation of T cells results in the induction of IFN-γ

Perspective

Mononuclear phagocytes are versatile, plastic cells that respond to environmental influences with the expression of distinct transcriptional programs and functions. The available information suggests that macrophages that infiltrate tumors acquire the properties of a polarized M2 phagocyte population.

The view of TAMs as a skewed M2 macrophage population is an oversimplification. Indeed, tumors are a diverse set of disorders, and a systematic effort of in vitro and in vivo characterization has

Poster

For more information on macrophage development and differentiation, see our Trends in Immunology poster at http://archive.bmn.com/supp/imto/posterv23i4.pdf.

References (74)

S. Goerdt
Other functions, other genes: alternative activation of antigen-presenting cells
Immunity
(1999)
A. Mantovani
The origin and function of tumor-associated macrophages
Immunol. Today
(1992)
F. Balkwill
Inflammation and cancer: back to Virchow?
Lancet
(2001)
A. Mantovani
The chemokine system: redundancy for robust outputs
Immunol. Today
(1999)
R. Bonecchi
Divergent effects of IL-4 and interferon-γ on macrophage-derived chemokine (MDC) production: an amplification circuit of polarized T helper 2 responses
Blood
(1998)
B. Barleon
Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the flt-1/VEGF receptor
Blood
(1996)
M.C. Duyndam
Vascular endothelial growth factor-165 overexpression stimulates angiogenesis and induces cyst formation and macrophage infiltration in human ovarian cancer xenografts
Am. J. Pathol.
(2002)
G. Opdenakker
Chemotactic factors, passive invasion and metastasis of cancer cells
Immunol. Today
(1992)
S. Scarpino
Papillary carcinoma of the thyroid: hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells
Am. J. Pathol.
(2000)
A. van den Berg
High expression of the CC chemokine TARC in Reed-Sternberg cells. A possible explanation for the characteristic T-cell infiltrate in Hodgkin's lymphoma
Am. J. Pathol.
(1999)

J. Cossman

Reed-Sternberg cell genome expression supports a B-cell lineage

Blood

(1999)

E. Schutyser

Identification of biologically active chemokine isoforms from ascitic fluid and elevated levels of CCL18/pulmonary and activation-regulated chemokine in ovarian carcinoma

J. Biol. Chem.

(2002)

M.R. Young

Human squamous-cell carcinomas of the head and neck chemoattract immune suppressive CD34(+) progenitor cells

Hum. Immunol.

(2001)

A.P. Vicari

Chemokines in cancer

Cytokine Growth Factor Rev.

(2002)

C. Menetrier-Caux

Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor

Blood

(1998)

L.M. Coussens

MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis

Cell

(2000)

K.L. Talks

The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages

Am. J. Pathol.

(2000)

A. Mantovani

Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines

Trends Immunol.

(2001)

M. Stein

Interleukin-4 potently enhances murine mannose receptor activity: a marker of alternative immunologic macrophage activation

J. Exp. Med.

(1992)

C.D. Mills

M-1/M-2 macrophages and the Th1/Th2 paradigm

J. Immunol.

(2000)

Hamilton, T.A. (2002) Molecular basis of macrophage activation: from gene expression to phenotypic diversity. In The...

K. Watanabe

Eotaxin-2 generation is differentially regulated by lipopolysaccharide and IL-4 in monocytes and macrophages

J. Immunol.

(2002)

V. Kodelja

Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 α with a Th2-associated expression pattern

J. Immunol.

(1998)

B. Rollins

Chemokines and Cancer

(1999)

J. Yang

Constitutive IκB kinase activity correlates with nuclear factor-κB activation in human melanoma cells

Cancer Res.

(2001)

B. Bottazzi

Regulation of the macrophage content of neoplasms by chemoattractants

Science

(1983)

M. Nesbit

Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in nontumorigenic melanoma cells

J. Immunol.

(2001)

E. Azenshtein

The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity

Cancer Res.

(2002)

H. Haghnegahdar

The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma

J. Leukocyte Biol.

(2000)

R. Bonecchi

Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes

J. Immunol.

(2000)

E.Y. Lin

Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy

J. Exp. Med.

(2001)

A. Adini

Placental growth factor is a survival factor for tumor endothelial cells and macrophages

Cancer Res.

(2002)

A. Nowicki

Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma

Int. J. Cancer

(1996)

M. Locati

Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes

J. Immunol.

(2002)

M.P. Keane

The role of CXC chemokines in the regulation of angiogenesis

J.M. Wang

Purification and identification of chemokines potentially involved in kidney-specific metastasis by a murine lymphoma variant: induction of migration and NFκB activation

Int. J. Cancer

(1998)

A. Muller

Involvement of chemokine receptors in breast cancer metastasis

Nature

(2001)

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Trends in Immunology

ReviewMacrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes

Abstract

Section snippets

Properties of polarized M1 and M2 macrophages

Recruitment

Links to adaptive immunity: the IL-10–TGF-β connection

Perspective

Poster

Immunity

Immunol. Today

Lancet

Immunol. Today

Blood

Blood

Am. J. Pathol.

Immunol. Today

Am. J. Pathol.

Am. J. Pathol.

Blood

J. Biol. Chem.

Hum. Immunol.

Cytokine Growth Factor Rev.

Blood

Cell

Am. J. Pathol.

Trends Immunol.

Interleukin-4 potently enhances murine mannose receptor activity: a marker of alternative immunologic macrophage activation

J. Exp. Med.

M-1/M-2 macrophages and the Th1/Th2 paradigm

J. Immunol.

Eotaxin-2 generation is differentially regulated by lipopolysaccharide and IL-4 in monocytes and macrophages

J. Immunol.

Alternative macrophage activation-associated CC-chemokine-1, a novel structural homologue of macrophage inflammatory protein-1 α with a Th2-associated expression pattern

J. Immunol.

Chemokines and Cancer

Constitutive IκB kinase activity correlates with nuclear factor-κB activation in human melanoma cells

Cancer Res.

Regulation of the macrophage content of neoplasms by chemoattractants

Science

Low-level monocyte chemoattractant protein-1 stimulation of monocytes leads to tumor formation in nontumorigenic melanoma cells

J. Immunol.

The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity

Cancer Res.

The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma

J. Leukocyte Biol.

Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes

J. Immunol.

Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy

J. Exp. Med.

Placental growth factor is a survival factor for tumor endothelial cells and macrophages

Cancer Res.

Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma

Int. J. Cancer

Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes

J. Immunol.

The role of CXC chemokines in the regulation of angiogenesis

Purification and identification of chemokines potentially involved in kidney-specific metastasis by a murine lymphoma variant: induction of migration and NFκB activation

Int. J. Cancer

Involvement of chemokine receptors in breast cancer metastasis

Nature

Review
Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes