Abstract
Chemokine receptors are G-protein-coupled, seven-transmembrane-spanning surface receptors that are play key roles in cell trafficking, cell motility, and survival. These receptors are activated by small molecular weight chemotactic cytokines called chemokines. Chemokine receptors play roles in the migration and localization of normal T cells (and other leukocytes) during physiologic responses in inflamed or infected skin. In cancer cells, these receptors may also facilitate tumorigenesis, metastasis, and resistance to immune-mediated killing. This review will focus on recent data that reveal potential roles of specific chemokine receptors, including CCR4, CXCR4, and CCR10, in the pathophysiology of cutaneous T cell lymphoma (CTCL), including mycosis fungoides and Sézary syndrome.
Introduction
The cutaneous T cell lymphomas (CTCL) represent a diverse group of skin-localized lymphomas (Hwang et al., 2008). Diverse in clinical presentation, most tend to be indolent and limited in distribution, although some forms can be rapidly progressive and eventuate in systemic involvement. The CTCL entities known classically as mycosis fungoides (MF, presenting with patches, plaques, tumors) and Sézary syndrome (SS, presenting with leukemic T cells in the blood and erythroderma) comprise the large majority of CTCL cases (Criscione and Weinstock, 2007). There has been substantial progress in understanding the pathogenesis of MF and SS although the etiology of these two diseases is still unknown.
The immunological abnormalities present in CTCL have been reviewed in detail by several groups (Hwang et al., 2008; Kim et al., 2005)). In most cases of MF and SS, a clonal expansion and activation of CD4-positive T cells results in the release of cytokines and growth factors that stimulate the proliferation of the epidermal keratinocytes (resulting in thickening and/or scaling of the skin) and inflammation in the epidermal and dermal compartments of skin (leading to erythema) (Kim et al., 2005). How malignant T cells are able to localize so specifically to skin remains one of the most fascinating questions in the CTCL field. Recent data from Campbell et al. (Campbell et al., 2007)and others focus on a family of chemotactic receptors called “chemokine receptors” that affect the homing of T cells to skin under inflammatory conditions.
In the remainder of this overview, we will review the roles of chemokine receptors in the biology of CTCL Herein, we will emphasize that chemokine receptors influence not only migration, but also the survival of malignant cells in the skin by activating prosurvial pathways that act independently of migratory/adhesive pathways.
Chemokines and Chemokine Receptors in CTCL Pathophysiology
The chemokines are a large group of chemotactic proteins (~8–11 kDa in size) that are grouped into four families (C, CC, CXC, and CX3C) based on the spacing of amino-terminal cysteine residues (Charo and Ransohoff, 2006). The chemokines (and their receptors) are generally known by their systematic names, consisting of the family of the chemokine followed by the letter “L”, for ligand, or “R”, for receptor, and a number indicating their order of discovery. The CC and CXC families form the majority of known chemokines (currently ~50). Chemokines interact with cell surface, 7-transmembrane domain, G-protein-coupled receptors. So far, more than 18 chemokine receptors have been described. Some chemokine receptors bind to multiple chemokines and vice versa, suggesting functional redundancies within this protein family. Within the limited scope of this review, we will discuss recent data regarding the role of selected chemokine receptors in CTCL patholophysiology. These receptors (CCR4, CCR10, CCR7, and CXCR4) have been implicated by more than human expression data to have potential novel roles in CTCL. Other potentially relevant chemokine receptors are listed in Table 1.
Table I.
Chemokine receptors and selected chemokine ligands with potential involvement in CTCL. The cells that express the indicated receptor or ligand are indicated in brackets.
Chemokine Receptor [Expression pattern] | Ligand(s) [Expression pattern] | Evidence for Roles in CTCL Pathophysiology |
---|---|---|
CCR3 (a promiscuous receptor) [T cells, eosinophils, other leukocytes] | CCL5, 7, 8, 11 and others [Macrophages and other cells] | CCR3 is expressed in CD30+ skin lymphoma (Kleinhans et al., 2003). |
CCR4 [T cells] | CCL17, CCL22 [Keratinocytes, DC, endothelial cells] | CCR4 is involved in T cell trafficking to skin (Campbell et al., 2007). Its expression is increased in CLA+ T cells in CTCL patients (Ferenczi et al., 2002) and is enhanced along with CCR10 and CCR7 in SS patients(Sokolowska-Wojdylo et al., 2005). CCR4 expression is also observed in large cell transformation of MF tumors (Jones et al., 2000). |
CCR10 [Skin-homing T cells, melanocytes] | CCL27 [Endothelial cells and keratinocytes] | CCR10 is critical to T cell trafficking to skin under inflammatory conditions (Homey et al., 2002) and is expressed by malignant cells in MF and SS (Notohamiprodjo et al., 2005). |
CXCR3[Memory T cells and NK cells] | CXCL9,10,11 [Keratinocytes, endothelial cells, fibroblasts, monocytes] | CXCR3 is expressed in low-grade MF (Lu et al., 2001) |
CCR7 [DC, T cells] | CCL21 [Lymphatic endothelial cells, LN endothelial cells] | CCR7 and CCL21 are instrumental in physiologic homing of T cells to LN (Förster et al., 1999; Gunn et al., 1999); CCR7 shows high expression by malignant MF and SS cells; it may facilitate nodal metastasis (Kallinich et al., 2003); increased expression of CCR7 is associated with LN infiltration in adult T cell leukemia-lymphoma (Hasegawa et al., 2000). |
CXCR4 [Endothelial cells, leukcytes, and many other cell types] | CXCL12 [Stromal cells, including fibroblasts as well as other cells] | Skin homing may involve CXCR4 signaling and down-regulation of CD26, a protease that cleaves CXCL12 (Narducci et al., 2006) |
Chemokines are noteworthy for their ability to stimulate directional migration of nearly all classes of leukocytes. T cells from different functional subsets (e.g., Th1, Th2, Th17, Treg, naïve vs. memory, etc.) express a regulated set of chemokine receptors that allow them to differentially respond to specific chemokines. Epidermal keratinocytes are capable of expressing multiple chemokines (see Fig. 1) that can attract a wide rage of leukocytes, including T cells, to the epidermis (Schön and Ruzicka, 2001). In addition to stimulating migration toward the epidermis, chemokines increase the affinity and avidity of β1 and β2 integrins on leukocytes for their endothelial counter-receptors such as ICAM-1. In vivo, chemokine-dependent integrin activation leads to firm adherence of leukocytes on the luminal surfaces of vascular endothelial cells, which produce chemokines themselves or acquire them from other cells in the inflammatory milieu for “presentation” on endothelial cell surface proteoglycans (Fig. 1).
Fig. 1. Roles for chemokines in CTCL pathyphysiology and therapy.
Malignant T cells in CTCL have been shown to express a relatively small number of chemokine receptors. Endothelial cells (EC), keratinocytes (KC), and dendritic cells (DC) all produce a variety of chemokines that can regulate the homing (1) of malignant (and normal) T cells via changes in EC-adhesion, stimulated chemotaxis toward epidermis, or movement toward activating DC, respectively. DC produce chemokines that mediate their adhesion to T cells (e.g., Pautrier’s microabscesses), thus stimulating activation (2) of these T cells. KC- and DC-derived chemokines have the potential to activate prosurvival pathways that diminish the capacity of T cells to undergo apoptosis (3). Therapeutically, chemokine-tagged T cell antigens (4) that are processed by skin DC have the potential to act as vaccines to enhance a host anti-tumor immunity toward malignant T cells. Chemokine-tagged toxins (5) have the potential to directly induce cell death in malignant T cells bearing appropriate receptors (e.g., CCR4).
Chemokines produced by other cells, namely epidermal and dermal dendritic cells (DC) bearing yet-unidentified skin antigens, may also play important roles in attracting malignant T cells to form conjugates with these antigen-presenting cells, leading to subsequent T cell activation (Fig. 1).Experimental data indicate that DC synthesize CCR4 ligands which rapidly stimulate chemotaxis of (or conjugate formation with) normal T cells (Tang and Cyster, 1999; Wu et al., 2001). DC-malignant T cell conjugates known as “Pautrier’s microabscesses” are specific histopathologic markers for MF and may be initiated by DC-derived chemokines. The involvement of DC in CTCL pathophysiology has been extensively reviewed by others (Edelson, 2001).
The chemokine receptors CCR4 and CCR10 have both been reported to participate in trafficking of T cells to the skin under inflammatory conditions (Homey, 2005; Reiss et al., 2001). Both are selectively expressed by so-called “skin-homing” memory T cells (a subset of the total memory T cells) that bear surface carbohydrate ligands to E-selectin, an adhesion protein that is characteristically expressed by inflamed dermal blood vessels. Neutralizing antibodies to CCL27 (the CCR10 ligand) dramatically reduces contact dermatitis in murine models (Homey et al., 2002).
The role of CCR4, however, was somewhat less clear because optimal inhibition of cutaneous inflammation in CCR4-deficient mice was obtained only when CCL27 antagonists were given (Reiss et al., 2001). Recent data indicate that CCR4 plays a critical role in antigen-dependent T cell-mediated inflammation in the skin since only CCR4 wild type T cells specific for OVA peptide were able to accumulate efficiently in skin in response to ovalbumin peptide (Campbell et al., 2007). Importantly, Campbell et al. showed that adoptive transfer of CCR4-deficient OVA-specific T cells in antigen-treated mice resulted in the same increase in the peripheral pool of OVA-specific, E-selectin ligand+ T cells as did CCR4 wild type antigen-specific T cells (Campbell et al., 2007). Thus, the failure to accumulate OVA-specific CCR4-negative T cells in the skin was likely to be attributable to a trafficking defect to the skin. This data was supported by their observation that CCR4-negative T cells home normally to the gut, thus ruling out an intrinsic homing defect in these cells (Campbell et al., 2007). While one must be cautious about applying the results of murine studies to human physiology, a fair number of clinical observational studies suggest that CCR4 is generally very highly expressed among CTCL cells in by MF and SS (Table I).
There is increasing evidence that cancer cells can use chemokine receptors to alter their metastatic spread. Mechanistically, chemokine receptors can alter the ability of cancer cells to arrest on vascular endothelial cells (Cardones et al., 2003). Moreover, chemokine receptor engagement results in the activation of well-characterized prosurvival pathways such as phosphatidylinositol-3-kinase (PI3K) and Akt (Kakinuma and Hwang, 2006). The prosurvival function of chemokine receptors in cancer cells is supported by data showing that melanoma cells use CXCR4 and CCR10 to enhance cell survival in the absence of serum or in the face of immune attack (Kakinuma and Hwang, 2006). With CCR10, activation of PI3K was required for chemokine receptor activation to inhibit Fas- and T cell-dependent killing of melanoma cells in vitro. In T cells, chemokine receptor activation suppressed cyclohexamide- and serum deprivation-induced apoptosis (Diaz-Guerra et al., 2007; Youn et al., 2002). With very high concentrations of chemokine in vitro, however, chemokine receptor activation in T cells may actually block proliferation (Ziegler et al., 2007). Thus, the prosurvival functions of chemokine receptors, in addition to their migratory functions, may also play a role in the ability of local chemokines to determine the composition of inflammatory cells at a particular site of inflammation or infection (Fig. 1).
While only ~25% of circulating CD3+, CD4+ T cells express CCR4 (Narducci et al., 2006), CCR4 has been shown to be much more frequently expressed on MF as well as SS cells (see Fig. 3A) (Ferenczi et al., 2002; Narducci et al., 2006). CCL17, a CCR4 ligand, is produced by activated keratinocytes, endothelial cells, and DC, and is up-regulated in the epidermis and serum of patients with MF (Kakinuma et al., 2003). Like CCL17, CCL27 (a CCR10 ligand) is increased in the serum of MF/SS patients and can be a marker of disease activity (Kagami et al., 2006). The CCL27 receptor, CCR10, is only infrequently expressed on peripheral blood T cells, but it is enriched in CLA+ skin-homing T cells and in CTCL cells (Homey et al., 2002; Notohamiprodjo et al., 2005). CCL27, however, is constitutively present in epidermal keratinocytes (basal layer) under basal, non-inflammatory conditions (Fig. 2) and may play a role in T cell epidermotropism in MF. Recent evidence from our laboratory suggests that CCL27 can be rapidly released from activated keratinocytes, thus regulating cutaneous as well as nodal homing of T cells following transfer of CCL27 to regional lymph nodes (LNs) via the afferent lymphatics (Huang et al., 2008). CCR7, a receptor that appears to be critical for migration of maturing skin dendritic cells and selected T cell subsets to the LNs (Forster et al., 1999), is also expressed at fairly high levels in Sézary cells (Sokolowska-Wojdylo et al., 2005) and may play a role in the tropism of these cells to peripheral LNs, which constitutively synthesize CCR7 ligands (i.e., CCL19 and 21).
Fig. 2. CCL27 expression in normal human skin.
Frozen sections of normal human skin with stained with fluorescent (green) monoclonal antibody specific for human CCL27 (A) or with a control isotype mouse IgG (B). Sections were counterstained with DAPI to visualize nuclei. The dashed white lines indicate the approximate location of the epidermal basement membrane.
The CXCR4 chemokine receptor may also play a role in homing of MF and SS cells. Loss of cell surface antigens, including CD7 and CD26, has been recognized as characteristic of MF and SS (Scala et al., 1999). The down-regulation of CD26, a dipeptidylpeptidase, is particularly interesting because CD26 cleaves and inactivates CXCL12, a CXCR4 ligand produced by stromal cells and fibroblasts in the dermis. Inactivation of CD26 enhanced CXCL12-driven chemotaxis of cell lines derived from SS patients (Narducci et al., 2006), whereas soluble CD26 inhibited CXCR4-mediated migration. Thus, the loss of CD26 on the Sézary cells may increase their ability to migrate to and/or survive in the skin.
Chemokine Receptors as Therapeutic Targets in CTCL
Targeting CCR4 and CCR10, the two chemokine receptors which appear to be frequently expressed by CTCL cells, may be a novel therapeutic strategy for treating CTCL. It is currently unknown whether targeting these two receptors, which are expressed by normal skin-homing T cells, would result in significant immunosuppression. A relatively small fraction of the total T cell population expresses these receptors. Thus, eradication of CCR4 and CCR10-positive T cell populations would not render patients severely lymphopenic.
Small molecule antagonists of CCR4 and CCR10 have yet to be developed, but antibodies CCR4 that induce antibody-dependent cellular cytotoxicity have already been reported (Ishida et al., 2004; Yano et al., 2007). Furthermore, Rook et al. reported that bexarotene down-regulates CCR4 expression and/or function, suggesting another mechanism by which bexarotene is effective in CTCL (Richardson et al., 2007). Novel chemokine-toxin fusion proteins analogous to the IL-2-diphtheria toxin fusion protein (denileukin diftitox) may be highly specific for skin-homing T cell populations if they used chemokines such as CCL17 or CCL27 to direct binding to cutaneous T cells (Fig. 1). Ligation of the chemokine receptor with a fusion toxin would result in endocytosis of the chemokine-toxin and cell death. CCL17 molecules fused to the Pseudomonas exotoxin 38 (PE38) have already been shown to effectively kill lymphoma cells that express CCR4 (Baatar et al., 2007) and thus they may prove useful as therapeutic agents in MF and/or SS. The in vitro inhibition of growth of a cell line derived from a SS patient by CCL17-PE38 is shown in Fig. 3B.
Fig. 3. CCL17-PE38 chemotoxin kills CCR4-positive T cells isolated from a patient with Sézary syndrome.
CD4+ T cells were isolated from the peripheral blood of a patient with SS. (A) >80% of CD4-gated T cells expressed CCR4 as determined by flow cytometry using a CCR4-specific monoclonal antibody. For comparison, ~25% of CD4+ T cells in healthy controls express CCR4 (Narducci et al., 2006). (B) CD4+ SS cells from a patient were exposed to PBS or CCL17-PE chemotoxin (7 ug/ml, courtesy of Dr. Arya Biragyn, National Aging Institute)(Baatar et al., 2007) for three days and then assessed for viability using a vital dye stain (arbitrary optical density units).
Summary
Chemokine receptors are likely to be involved in the skin-tropism that characterizes CTCL. In addition to facilitating firm arrest of skin-homing T cells on dermal vascular endothelial cells, they provide directional cues for the migration of T cells to specific compartments of the skin, including the epidermis. Even after localizing in skin, chemokine receptors may increase the survival of T cell, both malignant and benign, through activation of well recognized survival pathways that inhibit apoptosis. The understanding of how chemokine receptors regulate trafficking and survival provides motivation for the use of receptor antagonists or anti-receptor antibodies as novel therapeutic agents.
Acknowledgments
Anke S. Lonsdorf is a recipient of a NIH-German Research Foundation (DFG) Career Transition Award.
Abbreviations
- CTCL
Cutaneous T cell lymphoma
- MF
mycosis fungoides
- SS
Sézary syndrome
- and LN
lymph node
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