Chemokines in the recruitment and shaping of the leukocyte infiltrate of tumors

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Abstract

Leukocytes, and macrophages in particular, are an important component of the stroma of neoplastic tissues. Tumor-associated macrophages (TAM) have the properties of a polarized M2 population and are a key component of inflammatory circuits which promote tumor growth and progression. Chemokines play a key role in the recruitment and positioning of TAM and dendritic cells in tumors and contribute to shaping their functional properties. Chemokine-recruited and positioned tumor infiltrating leukocytes are a key component of inflammatory circuits which promote tumor progression.

Introduction

Leukocytes infiltrate neoplastic tissues and are a manifestation of inflammation in the context of neoplastic disorders [1]. Mononuclear phagocytes are a major component of the leukocyte infiltrate of tumors [2]. Tumor-associated macrophages (TAM) have complex, dual functions in their interaction with neoplastic cells, but strong evidence suggests that they are part of inflammatory circuits that promote tumor progression.

Macrophage are versatile cells which respond and adapt to microenvironmental signals. Classic macrophage activation in response to microbial agents and cytokines, interferon-γ (IFNγ) in particular, has long been recognized [3]. More recently, it was realized that antiinflammatory 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) [4], [5], [6], [7]. In analogy with the Th1/Th2 dichotomy in T cell responses, macrophages exposed to IFNγ and IL-4 have also been referred to as M1 and M2 [8]. Available information suggests that classically activated type I macrophages (M1) are potent effector cells which kill microorganisms and tumor cells and produce copious amounts of proinflammatory cytokines. In contrast, type II macrophages (M2) tune inflammatory responses and adaptive Th1 immunity, scavenge debris, promote angiogenesis, tissue remodeling and repair. Recent information support the emerging view that TAM are a polarized type II (or M2 or alternatively activated) macrophage population [4], [5], [8]. The polarized functions of TAM integrate them in circuits of subversion of antitumor immunity and in inflammatory mechanisms which promote tumor growth and progression.

Chemokines play a key role in the recruitment and shaping of the leukocyte infiltrate of tumors. Historically, tumor cells have been invaluable for the discovery and characterization of components of the chemokine system. Here we will review how chemokines direct migration of leukocytes in neoplastic tissue and how they contribute to shaping the functional properties of infiltrating cells, with a focus on TAM and tumor-associated dendritic cells (DC).

Section snippets

Chemokines in polarized macrophage populations

Components of the chemokine network are differentially modulated in polarized macrophages. IL-10 up-regulates the CC chemokine receptors CCR1, CCR2 and CCR5. In contrast, CXCR2 and CXCR4 are partially down-regulated under the same conditions [9]. An increase of CCR2 expression is also observed in monocytes exposed to dexamethasone [10]. IL-4 and IL-13 do not modify the expression of CC chemokine receptors but induce functional CXCL8 (IL-8) receptors in human monocytes [11]. On the contrary,

Chemokines involved in macrophage infiltration

TAM 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 [20]. Several lines of evidence, including correlation between production and infiltration in murine and human tumors, passive immunization and gene modification, indicate that chemokines play a pivotal role in the recruitment of monocytes in neoplastic tissues [21]. Indeed, tumors have been invaluable for

Positioning of macrophages in hypoxic areas

Uneven vascularization and hypoxia are characteristics of neoplastic tissues which affect macrophage distribution and function. TAM accumulate preferentially in the poorly vascularized region of tumors which are characterized by low oxygen tension. Recent studies have shown that macrophage migration is suppressed in hypoxic condition [39], [40] and that TAM are immobilized in avascular [41] and necrotic hypoxic areas of tumors [42]. Evidence suggests that in hypoxia TAM are stimulated to

Chemokines and adaptive antitumor immunity

As mentioned above, chemokines are more than leukocyte attractants. Chemokine are part of amplification and regulation systems of polarized T cell responses. Work in gene-modified mice has shown that CCL2, produced by a variety of tumors, can orient specific immunity in a Th2 direction, although the exact mechanism for this action has not been defined [49]. It may include stimulation of IL-10 production in macrophages. In addition to being produced by neoplastic cells, CCL2 is also expressed at

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