Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells

Abstract

IntroductionCirculating monocytes are precursors that can differentiate into a variety of tissue-resident macrophages (M⌽s) or dendritic cells (DCs), and even osteoclasts. 1 M⌽s exhibit a variety of activities, some of which are in opposition (ie, proinflammatory versus anti-inflammatory, immunostimulatory versus immunosuppressive, and tissue destructive versus reconstructive). 1 The functional heterogeneity of M⌽s depends, at least in part, on the local microenvironment. 2,3 In analogy with the Th1/Th2 dichotomy of T-cell responses, M⌽s exposed to IFN␥ or IL-4 have been referred to as M1s or M2s (also called alternatively activated M⌽s), respectively. 4 M1s produce IL-12 and TNF␣ and are potent killers of microorganisms (especially intracellular pathogens) and tumor cells. M2s produce IL-10 but not IL-12, scavenge debris, tune inflammatory responses, and promote humoral immunity and tissue repair. 5 The detection in cancer patients of tumor-specific T cells that kill ex vivo autologous tumor cells demonstrates that numerous tumor-cell types are potentially immunogenic. However, spontaneous clearance of established tumors by immune mechanisms is rare and active antitumor immunotherapy usually has poor clinical efficacy. 6 It is now largely documented that established tumors propagate conditions that favor their immune escape. 6 Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) accumulate at tumor sites and maintain immune tolerance that contributes to defeating tumor immunity. 6,7 TAMs are far more abundant than Tregs and, in various solid tumors, constitute the major components of the leukocyte infiltrate. In most cases, especially breast, prostate, cervical, and ovarian cancers, TAM density is correlated with poor prognosis. [8][9][10] Strong evidence suggests that TAMs also promote cancer progression and metastasis. 8,11,12 TAMs are polarized M2 cells with potent immunosuppressive functions. They have poor antigen-presenting capacity, prevent T-cell activation, and may contribute to suppressing DC functions. 4,13,14 They also promote the recruitment of Tregs and Th2 cells (through CC chemokine ligand 17 [CCL17] and CCL22 secretion) and naive T cells (through CCL18). Naive T-cell activation, in an environment dominated by immature DCs and TAMs, is likely to induce anergy. 10,15 In addition, TAM production of growth and angiogenic factors (ie, vascular endothelial growth factor [VEGF] and platelet-derived endothelial cell growth factor [PDGF]), proteases (ie, matrix metalloproteinase 9 [MMP9]), and chemokines (eg, CCL2) favors tumor-cell proliferation, angiogenesis, dissolution of connective tissues, and metastasis. 8,12,14,16 The origin of TAMs has mostly been studied in mice in terms of precursor recruitment, survival, and proliferation. TAMs derive from circulating monocytes that are recruited into tumors by chemotactic factors, such as monocyte-colony-stimulating factor Submitted February 19, 2007; accepted August 29, 2007. Prepublished online as Blood First Edition paper, September 11, 2...

Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2

“…Compelling evidence has emerged in recent years showing macrophages being recruited to sites of solid tumor formation in vivo in response to chemoattractant signals, such as M-CSF and MCP-1, secreted by cancer cells and fulfilling an important role in tumor invasion into surrounding normal tissues, proliferation and survival, and metastasis to local and distant sites (Varney et al, 2002;Duluc et al, 2007;Fujimoto et al, 2009). Our results provided the first evidence that M-CSF þ MCP-1 and the structurally distinct FPR2 ligands induced monocyte differentiation into different M2 subtypes.…”

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…60 For this concern, to identify strategies that may inhibit their recruitment, block their generation, reverse their trophic and immunosuppressive roles or interfere with their survival may represent new therapeutic opportunities. 10 As a matter of fact, our study identifying the role of membrane CD39 in the acquisition and maintenance of an immunosuppressive phenotype by M-CSF-macrophages and TAM, could define ATP metabolism and IL-27 as privileged targets. 54,55 Experimental procedures / materials and methods Mononuclear cells were isolated using standard Lymphocyte Separation Medium (PAA Laboratories, Pashing, Austria).…”

“…Newly recruited monocytes in the tumor are in contact with ATPderived nucleotides which may participate to the acquisition of an IL-10 high IL-12 low immunosuppressive phenotype. 10,60 As CD39 is located upstream the ATP metabolism, we hypothesized that manipulating the ATP/AMP ratio may modulate the immunosuppressive properties of M-CSF-macrophages. Accordingly, we observed that CD39 inhibition or adenosine depletion enhanced the capacity of activated TAM and M-CSF-macrophages to produce IL-1b and reduced their capacity to produce IL-10.…”

“…9 We have previously reported that the CD115 ligands M-CSF and IL-34, drive monocytes into IL-10 high IL-12 low immunoregulatory macrophages which are similar to ovarian cancer TAM. 5,10,11 They represent a robust model to decipher in vitro the biology of immunoregulatory macrophages.…”

Human Renal Cell Carcinoma Induces a Dendritic Cell Subset That Uses T-Cell Crosstalk for Tumor-Permissive Milieu Alterations

“…These factors are highly expressed in RCC 5,48 and may thus promote the differentiation of ercDCs in situ. The identification of these factors was based on a study design that was distinct from those reported by others 37,49,50 : cultivation supplements, IL-4, or GM-CSF, which are commonly used to differentiate DCs in vitro but do not represent a DC differentiation pathway in vivo, 12 were deliberately omitted. Thus, we believe that the used cultivation system better reflected the natural process of monocyte differentiation when entering the tissue milieu.…”