A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF- B and enhanced IRF-3/STAT1 activation)

Biswas, Subhra K.; Gangi, Lisa; Paul, Saki; Schioppa, Tiziana; Saccani, Alessandra; Sironi, Marina; Bottazzi, Barbara; Doni, Andrea; Bronte, Vincenzo; Pasqualini, Fabio; Vago, Luca; Nebuloni, Manuela; Mantovani, Alberto; Sica, Antonio

doi:10.1182/blood-2005-01-0428

Cited by 613 publications

(530 citation statements)

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“…Recent reports have established that the acquisition of protumoral M2 functions by TAM is driven by various cytokines and signals expressed within the tumor microenvironment [3]. Among these, IL-10, PGE2, TGF-b and CSF-1 were reported to induce the M2-polarization of macrophages [3][4][5]. Based on the In a model of mammary carcinoma, myeloid-derived suppressor cells were shown to contribute to tumor progression by suppressing T-cell activation and inducing an M2-like phenotype of TAM, (increased IL-10 and decreased IL-12 production) [10].…”

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confidence: 99%

“…Recent reports have established that the acquisition of protumoral M2 functions by TAM is driven by various cytokines and signals expressed within the tumor microenvironment [3]. Among these, IL-10, PGE2, TGF-b and CSF-1 were reported to induce the M2-polarization of macrophages [3][4][5]. Based on the M1 versus M2 paradigm of macrophage polarization [6], inhibition of M2-and activation of M1-inducing signals (e.g.…”

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confidence: 99%

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Convergent pathways of macrophage polarization: The role of B cells

et al. 2010

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The construction of an inflammatory microenvironment provides the fuel for cancer development and progression. Hence, solid tumors promote infiltration of leukocyte populations, among which tumor-associated macrophages (TAM) represent a paradigm for cancer-promoting inflammation. TAM orchestrate various aspects of cancer, including diversion and skewing of adaptive responses, cell growth, angiogenesis, matrix deposition and remodelling, the construction of a metastatic niche and actual metastasis, response to hormones and chemotherapeutic agents. Several lines of evidence indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, suggesting that during tumor progression macrophages undergo a phenotypic ''switch'', eventually exhibiting the alternatively activated, ''M2'', phenotype that is associated with immunosuppression, promotion of tumor angiogenesis and metastasis. Although recent studies have attempted to address the role of microenvironmental signals on TAM ''reprogramming'', the interplay between innate and adaptive immunity is emerging as a crucial step of this event. In this issue of the European Journal of Immunology, a study demonstrates that B1 lymphocytes expressing IL-10 play a key role in promoting a pro-tumoral M2-biased phenotype of macrophages. This article defines a new in vivo pathway of macrophage polarization and suggests that targeting B cells is a possible therapeutic intervention to reinstate anticancer functions by TAM. Clinical and experimental evidence has highlighted that a major leukocyte population present in tumors, the so-called tumorassociated macrophages (TAM), is the principal component of the leukocyte infiltrate supporting tumor growth [1]. As macrophages represent a primary line of the innate or front-line defense mechanisms, this evidence has also underlined the ''immune paradox'' represented by TAM [2]. Over the past years, the mechanisms supporting the pro-tumoral functions of TAM have been increasingly clarified and in several experimental tumor models, the activation of an inflammatory response (most frequently mediated by macrophages) has been shown to play an essential role for full neoplastic transformation and progression. Recent reports have established that the acquisition of protumoral M2 functions by TAM is driven by various cytokines and signals expressed within the tumor microenvironment [3]. Among these, IL-10, PGE2, TGF-b and CSF-1 were reported to induce the M2-polarization of macrophages [3][4][5]. Based on the In a model of mammary carcinoma, myeloid-derived suppressor cells were shown to contribute to tumor progression by suppressing T-cell activation and inducing an M2-like phenotype of TAM, (increased IL-10 and decreased IL-12 production) [10].The role of B cells in solid tumor development is well characterized, for example B-cell-deficient mice (mMT) exhibited resistance to several type of syngeneic tumors, including EL4 lymphoma, MC38 colon carcinoma and B16 or D5 melanoma [9]. A first original report on B cells and can...

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confidence: 99%

“…Recent reports have established that the acquisition of protumoral M2 functions by TAM is driven by various cytokines and signals expressed within the tumor microenvironment [3]. Among these, IL-10, PGE2, TGF-b and CSF-1 were reported to induce the M2-polarization of macrophages [3][4][5]. Based on the M1 versus M2 paradigm of macrophage polarization [6], inhibition of M2-and activation of M1-inducing signals (e.g.…”

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confidence: 99%

Convergent pathways of macrophage polarization: The role of B cells

et al. 2010

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“…36 Thus the described phenotype fits well to ATM's excessive IL-10 and IL-Ra production. 38 In contrast to surface marker expression corresponding to anti-inflammatory M2-like cells, the large amounts of proinflammatory cytokines secreted by ATMs (Figure 5), in contrast to typical M2 macrophages, 39 support a role of ATMs in obesity-induced adipocyte dysfunction and metabolic disorders, although IL-Ra also may contribute to the onset of insulin resistance. 40 The high basal cytokine production of ATMs shown in this study does not necessarily imply that unstimulated ATMs secrete these large amounts of cytokines in situ, since ATMs could have been stimulated during their isolation and cultivation.…”

Section: Discussionmentioning

confidence: 92%

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

et al. 2007

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Objective: Obesity is associated with a chronic low-grade inflammation and an increased abundance of macrophages in adipose tissue. Adipose tissue macrophages (ATMs) are assumed to interfere with adipocyte function leading to insulin resistance, thereby contributing to the pathogenesis of type 2 diabetes mellitus. Macrophages exist in separate types of differentiation, but the nature of ATMs is largely unknown. Design and measurements: Stromal vascular cells (SVCs) and ATMs were isolated from human adipose tissues from different locations. We characterized ATMs phenotypically and functionally by flow cytometry, endocytosis assay and determination of secreted cytokines. For comparison, we used macrophages of the 'classical' (M1) and the 'alternative', anti-inflammatory (M2) type differentiated in vitro from peripheral blood monocytes. Results: Like prototypic M2 macrophages, ATMs expressed considerable amounts of mannose receptor, haemoglobin scavenger receptor CD163 and integrin avb5. The number of cells expressing these molecules correlated significantly with the donors' body mass indices (BMIs). Notably, SVCs positive for the common monocyte/macrophage marker CD14 contained a considerable fraction of blood monocytes, the abundance of which did not correlate with the BMIs, pointing to the requirement of the surface markers identified here for the identification of ATMs. ATMs showed endocytic activities similar to M2 macrophages and accordingly secreted high amounts of IL-10 and IL-1 receptor antagonist. However, basal and induced secretion of pro-inflammatory mediators TNF-a, IL-6, IL-1, MCP-1 and MIP-1a was even higher in ATMs than in proinflammatory M1 macrophages. Conclusion: ATMs comprise a particular macrophage type that is M2-like by surface marker expression, but they are competent to produce extensive amounts of inflammatory cytokines, which could considerably contribute to the development of insulin resistance.

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“…How do MDSC relate to monocyte and macrophage subsets or differentiation stages, such as the Tie2 + monocytes [12], tumour-associated macrophages Commentary and, more generally, polarized M2 macrophages [13]? Limited profiling data on conventional MDSC suggest a definite relationship with polarized M2 cells [14,15]. More ''omics'' data coupled with a focus on tissues may eventually solve some of these unresolved questions.…”

Section: Introductionmentioning

confidence: 99%

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

Mantovani

2008

Eur J Immunol

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In this issue of the European Journal of Immunology, Siamon Gordon gives a detailed account of Metchnikoff's life and his achievements (Eur. J. Immunol. 2008. 38: 3257-3264). Looking back at the roots of innate immunity stimulates reflections on open issues in the field. Here, I give a personal view of some of these issues, including myeloid-derived suppressor cells, macrophage polarization and adaptive responses of mononuclear phagocytes. Key words: Macrophage activation Á Macrophages Á M1/M2 polarization Á Probiotics See accompanying article by Gordon IntroductionIn his scholarly review [1], Siamon Gordon tracks the roots of innate immunity to Elie Metchnikoff. The essay provides a fascinating insight into Metchnikoff's scientific life and how he tackled fundamental issues in science, some of which remain with us to this day. The perspective offered by a major player in the very same field of phagocytes and innate immunity [2,3] adds flavour and fascination to this article not necessarily present in other accounts [4]. Such a reflection on a central part of modern immunology stimulates consideration of remaining open issues and there follows a personal view of some of these.Phagocyte heterogeneity: From microphage-macrophage dichotomy to myeloid-derived suppressor cellsThe fundamental distinction between polymorphonuclear leukocytes (microphages) and mononuclear phagocytes (macrophages) was a major first step in the dissection of phagocyte heterogeneity and lineage differentiation. The identification of myeloid-derived suppressor cells (MDSC) [5][6][7] raises the questions whether the classic sharp distinction between the myeloid and the monocyte-macrophage differentiation and activation pathways is appropriate. In contrast to long-held views, neutrophils express specific transcriptional programmes in response to environmental signals [8]. MDSC include immature myeloid precursors that can further differentiate, and play a key role in the suppression of adaptive immunity in diverse pathological conditions ranging from cancer to chronic infections [5][6][7]. Are we dealing with a blurring of a classic distinction or with a well-defined third phagocyte population? Using current identification and separation criteria (e.g. Gr1, CD11b, F4/80) MDSC in the blood and lymphoid organs are a mixed population, which includes myeloid cells at different stages of differentiation and mononuclear phagocytes. Thus, the definition of MDSC remains an operational one rather than that of a cell type, a reality that is frequently neglected. The issue of lineage of the actual effectors of MDSC-mediated suppression is even more relevant when their recruitment and activation in non-lymphoid tissues is considered. For instance, do MDSC retain an immature phenotype in tumour tissues or do they differentiate into tumourassociated macrophages [9][10][11] [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of i...

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A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF- B and enhanced IRF-3/STAT1 activation)

Cited by 613 publications

References 52 publications

Convergent pathways of macrophage polarization: The role of B cells

Convergent pathways of macrophage polarization: The role of B cells

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

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