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Cutaneous T-Cell Lymphoma: Roles for Chemokines and Chemokine Receptors

      Chemokine receptors are G-protein-coupled, seven-transmembrane-spanning surface receptors that 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 physiological 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, including mycosis fungoides and Sézary syndrome.

      Abbreviations

      CTCL
      cutaneous T-cell lymphoma
      DC
      dendritic cell
      MF
      mycosis fungoides
      SS
      Sézary syndrome
      LN
      lymph node

      Introduction

      The cutaneous T-cell lymphomas (CTCLs) represent a diverse group of skin-localized lymphomas (
      • Hwang S.
      • Janik J.
      • Jaffe E.
      • Wilson W.
      Mycosis fungoides and Sézary syndrome.
      ). 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 V.D.
      • Weinstock M.A.
      Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002.
      ). 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 (
      • Kim E.J.
      • Hess S.
      • Richardson S.K.
      • Newton S.
      • Showe L.C.
      • Benoit B.M.
      • et al.
      Immunopathogenesis and therapy of cutaneous T cell lymphoma.
      ;
      • Hwang S.
      • Janik J.
      • Jaffe E.
      • Wilson W.
      Mycosis fungoides and Sézary syndrome.
      )). 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 E.J.
      • Hess S.
      • Richardson S.K.
      • Newton S.
      • Showe L.C.
      • Benoit B.M.
      • et al.
      Immunopathogenesis and therapy of cutaneous T cell lymphoma.
      ). 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 J.J.
      • O’Connell D.J.
      • Wurbel M.A.
      Cutting edge: chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions.
      ) 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 prosurvival pathways that act independently of migratory/adhesive pathways.

      Chemokines and Chemokine Receptors In Ctcl Pathophysiology

      The chemokines are a large group of chemotactic proteins (∼8–11kDa in size) that are grouped into four families (C, CC, CXC, and CX3C) based on the spacing of amino-terminal cysteine residues (
      • Charo I.F.
      • Ransohoff R.M.
      The many roles of chemokines and chemokine receptors in inflammation.
      ). 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, seven-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 pathophysiology. 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 1Chemokine receptors and selected chemokine ligands with potential involvement in CTCL
      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 M.
      • Tun-Kyi A.
      • Gilliet M.
      • Kadin M.E.
      • Dummer R.
      • Burg G.
      • et al.
      Functional expression of the eotaxin receptor CCR3 in CD30+ cutaneous T-cell lymphoma.
      )
      CCR4 (T cells)CCL17, CCL22 (keratinocytes, DC, endothelial cells)CCR4 is involved in T-cell trafficking to skin (
      • Campbell J.J.
      • O’Connell D.J.
      • Wurbel M.A.
      Cutting edge: chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions.
      ). Its expression is increased in CLA+ T cells in CTCL patients (
      • Ferenczi K.
      • Fuhlbrigge R.C.
      • Pinkus J.
      • Pinkus G.S.
      • Kupper T.S.
      Increased CCR4 expression in cutaneous T cell lymphoma.
      ) and is enhanced along with CCR10 and CCR7 in SS patients (
      • Sokolowska-Wojdylo M.
      • Wenzel J.
      • Gaffal E.
      • Lenz J.
      • Speuser P.
      • Erdmann S.
      • et al.
      Circulating clonal CLA(+) and CD4(+) T cells in Sézary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymph node-homing chemokine receptor CCR7.
      ). CCR4 expression is also observed in large cell transformation of MF tumors (
      • Jones D.
      • O’Hara C.
      • Kraus M.D.
      • Perez-Atayde A.R.
      • Shahsafaei A.
      • Wu L.
      • et al.
      Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma.
      )
      CCR10 (skin-homing T cells, melanocytes)CCL27 (endothelial cells and keratinocytes)CCR10 is critical to T-cell trafficking to skin under inflammatory conditions (
      • Homey B.
      • Alenius H.
      • Muller A.
      • Soto H.
      • Bowman E.P.
      • Yuan W.
      • et al.
      CCL27-CCR10 interactions regulate T cell-mediated skin inflammation.
      ) and is expressed by malignant cells in MF and SS (
      • Notohamiprodjo M.
      • Segerer S.
      • Huss R.
      • Hildebrandt B.
      • Soler D.
      • Djafarzadeh R.
      • et al.
      CCR10 is expressed in cutaneous T-cell lymphoma.
      )
      CXCR3 (memory T cells and NK cells)CXCL9,10,11 (keratinocytes, endothelial cells, fibroblasts, monocytes)CXCR3 is expressed in low-grade MF (
      • Lu D.
      • Duvic M.
      • Medeiros L.J.
      • Luthra R.
      • Dorfman D.M.
      • Jones D.
      The T-cell chemokine receptor CXCR3 is expressed highly in low-grade mycosis fungoides.
      )
      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 R.
      • Schubel A.
      • Breitfeld D.
      • Kremmer E.
      • Renner-Müller I.
      • Wolf E.
      • et al.
      CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs.
      ;
      • Gunn M.D.
      • Kyuwa S.
      • Tam C.
      • Kakiuchi T.
      • Matsuzawa A.
      • Williams L.T.
      • et al.
      Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization.
      ); CCR7 shows high expression by malignant MF and SS cells; it may facilitate nodal metastasis (
      • Kallinich T.
      • Muche J.M.
      • Qin S.
      • Sterry W.
      • Audring H.
      • Kroczek R.A.
      Chemokine receptor expression on neoplastic and reactive T cells in the skin at different stages of mycosis fungoides.
      ); increased expression of CCR7 is associated with LN infiltration in adult T-cell leukemia–Lymphoma (
      • Hasegawa H.
      • Nomura T.
      • Kohno M.
      • Tateishi N.
      • Suzuki Y.
      • Maeda N.
      • et al.
      Increased chemokine receptor CCR7/EBI1 expression enhances the infiltration of lymphoid organs by adult T-cell leukemia cells.
      ).
      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 downregulation of CD26, a protease that cleaves CXCL12 (
      • Narducci M.G.
      • Scala E.
      • Bresin A.
      • Caprini E.
      • Picchio M.C.
      • Remotti D.
      • et al.
      Skin homing of Sézary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV.
      )
      The cells that express the indicated receptor or ligand are indicated in brackets.
      Chemokines are noteworthy for their ability to stimulate directional migration of nearly all classes of leukocytes. T cells from different functional subsets (for example, Th1, Th2, Th17, Treg, naïve vs memory, and so on) 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 Figure 1) that can attract a wide rage of leukocytes, including T cells, to the epidermis (
      • Schön M.P.
      • Ruzicka T.
      Psoriasis: the plot thickens.
      ). 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 intercellular adhesion molecule-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 (Figure 1).
      Figure thumbnail gr1
      Figure 1Roles 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. DCs produce chemokines that mediate their adhesion to T cells (for example, 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 antitumor immunity toward malignant T cells. Chemokine-tagged toxins (5) have the potential to directly induce cell death in malignant T cells bearing appropriate receptors (for example, 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 (Figure 1). Experimental data indicate that DC synthesize CCR4 ligands, which rapidly stimulate chemotaxis of, or conjugate formation with, normal T cells (
      • Tang H.L.
      • Cyster J.G.
      Chemokine up-regulation and activated T cell attraction by maturing dendritic cells.
      ;
      • Wu M.
      • Fang H.
      • Hwang S.T.
      Cutting Edge: CC chemokine receptor-4 (CCR4) mediates antigen-primed T cell binding to activated dendritic cells.
      ). DC-malignant T-cell conjugates known as “Pautrier's microabscesses” are specific histopathological 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 R.L.
      Cutaneous T cell lymphoma: the helping hand of dendritic cells.
      ).
      The chemokine receptors CCR4 and CCR10 have both been reported to participate in trafficking of T cells to the skin under inflammatory conditions (
      • Reiss Y.
      • Proudfoot A.E.
      • Power C.A.
      • Campbell J.J.
      • Butcher E.C.
      CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell- attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin.
      ;
      • Homey B.
      Chemokines and inflammatory skin diseases.
      ). 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 B.
      • Alenius H.
      • Muller A.
      • Soto H.
      • Bowman E.P.
      • Yuan W.
      • et al.
      CCL27-CCR10 interactions regulate T cell-mediated skin inflammation.
      ).
      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 Y.
      • Proudfoot A.E.
      • Power C.A.
      • Campbell J.J.
      • Butcher E.C.
      CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell- attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin.
      ). Recent data indicate that CCR4 plays a critical role in antigen-dependent T-cell-mediated inflammation in the skin, as only CCR4 wild-type T cells specific for ovalbumin peptide were able to accumulate efficiently in skin in response to ovalbumin peptide (
      • Campbell J.J.
      • O’Connell D.J.
      • Wurbel M.A.
      Cutting edge: chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions.
      ). Importantly,
      • Campbell J.J.
      • O’Connell D.J.
      • Wurbel M.A.
      Cutting edge: chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions.
      ) 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. 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 J.J.
      • O’Connell D.J.
      • Wurbel M.A.
      Cutting edge: chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions.
      ). 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 MF and SS patients (Table 1).
      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 A.R.
      • Murakami T.
      • Hwang S.T.
      CXCR4 enhances adhesion of B16 tumor cells to endothelial cells in vitro and in vivo via beta 1 integrin.
      ). Moreover, chemokine receptor engagement results in the activation of well-characterized prosurvival pathways such as phosphatidylinositol-3-kinase and Akt (
      • Kakinuma T.
      • Hwang S.T.
      Chemokines, chemokine receptors, and cancer metastasis.
      ). 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 T.
      • Hwang S.T.
      Chemokines, chemokine receptors, and cancer metastasis.
      ). With CCR10, activation of phosphatidylinositol-3-kinase 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 (
      • Youn B.S.
      • Yu K.Y.
      • Oh J.
      • Lee J.
      • Lee T.H.
      • Broxmeyer H.E.
      Role of the CC Chemokine receptor 9/TECK interaction in apoptosis.
      ;
      • Diaz-Guerra E.
      • Vernal R.
      • del Prete M.J.
      • Silva A.
      • Garcia-Sanz J.A.
      CCL2 inhibits the apoptosis program induced by growth factor deprivation, rescuing functional T cells.
      ). With very high concentrations of chemokine in vitro, however, chemokine receptor activation in T cells may actually block proliferation (
      • Ziegler E.
      • Oberbarnscheidt M.
      • Bulfone-Paus S.
      • Forster R.
      • Kunzendorf U.
      • Krautwald S.
      CCR7 signaling inhibits T cell proliferation.
      ). 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 (Figure 1).
      While only ∼25% of circulating CD3+ and CD4+ T cells express CCR4 (
      • Narducci M.G.
      • Scala E.
      • Bresin A.
      • Caprini E.
      • Picchio M.C.
      • Remotti D.
      • et al.
      Skin homing of Sézary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV.
      ), CCR4 has been shown to be much more frequently expressed on MF as well as SS cells (see Figure 3a) (
      • Ferenczi K.
      • Fuhlbrigge R.C.
      • Pinkus J.
      • Pinkus G.S.
      • Kupper T.S.
      Increased CCR4 expression in cutaneous T cell lymphoma.
      ;
      • Narducci M.G.
      • Scala E.
      • Bresin A.
      • Caprini E.
      • Picchio M.C.
      • Remotti D.
      • et al.
      Skin homing of Sézary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV.
      ). CCL17, a CCR4 ligand, is produced by activated keratinocytes, endothelial cells, and DC and is upregulated in the epidermis and serum of patients with MF (
      • Kakinuma T.
      • Sugaya M.
      • Nakamura K.
      • Kaneko F.
      • Wakugawa M.
      • Matsushima K.
      • et al.
      Thymus and activation-regulated chemokine (TARC/CCL17) in mycosis fungoides: serum TARC levels reflect the disease activity of mycosis fungoides.
      ). Similar to CCL17, CCL27 (a CCR10 ligand) is increased in the serum of MF/SS patients and can be a marker of disease activity (
      • Kagami S.
      • Sugaya M.
      • Minatani Y.
      • Ohmatsu H.
      • Kakinuma T.
      • Fujita H.
      • et al.
      Elevated serum CTACK/CCL27 levels in CTCL.
      ). 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 B.
      • Alenius H.
      • Muller A.
      • Soto H.
      • Bowman E.P.
      • Yuan W.
      • et al.
      CCL27-CCR10 interactions regulate T cell-mediated skin inflammation.
      ;
      • Notohamiprodjo M.
      • Segerer S.
      • Huss R.
      • Hildebrandt B.
      • Soler D.
      • Djafarzadeh R.
      • et al.
      CCR10 is expressed in cutaneous T-cell lymphoma.
      ). CCL27, however, is constitutively present in epidermal keratinocytes (basal layer) under basal, noninflammatory conditions (Figure 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 V.
      • Lonsdorf A.S.
      • Fang L.
      • Lee V.C.
      • Cha E.
      • Zhang H.
      • et al.
      Cutting edge: rapid accumulation of epidermal CCL27 in skin-draining lymph nodes following topical application of a contact sensitizer recruits CCR10-expressing T cells.
      ). CCR7, a receptor that appears to be critical for migration of maturing skin DCs and selected T-cell subsets to the LNs (
      • Forster R.
      • Schubel A.
      • Breitfeld D.
      • Kremmer E.
      • Renner-Muller I.
      • Wolf E.
      • et al.
      CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs.
      ), is also expressed at fairly high levels in Sézary cells (
      • Sokolowska-Wojdylo M.
      • Wenzel J.
      • Gaffal E.
      • Lenz J.
      • Speuser P.
      • Erdmann S.
      • et al.
      Circulating clonal CLA(+) and CD4(+) T cells in Sézary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymph node-homing chemokine receptor CCR7.
      ) and may play a role in the tropism of these cells to peripheral LNs, which constitutively synthesize CCR7 ligands (that is, CCL19 and 21).
      Figure thumbnail gr2
      Figure 2CCL27 expression in normal human skin. Frozen sections of normal human skin stained (a) with fluorescent (green) monoclonal antibody specific for human CCL27 or (b) with a control isotype mouse IgG. Sections were counterstained with 4′,6-diamidino-2-phenylindole to visualize nuclei. The dashed white lines indicate the approximate location of the epidermal basement membrane. Bar=10μm, which is indicated in the image on the left.
      Figure thumbnail gr3
      Figure 3CCL17-PE38 chemotoxin kills CCR4-positive T cells isolated from a patient with SS. 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 mAb. For comparison, ∼25% of CD4+ T cells in healthy controls express CCR4 (
      • Narducci M.G.
      • Scala E.
      • Bresin A.
      • Caprini E.
      • Picchio M.C.
      • Remotti D.
      • et al.
      Skin homing of Sézary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV.
      ). (b) CD4+ SS cells from a patient were exposed to PBS or CCL17-PE chemotoxin (7μgml-1, courtesy of Dr Arya Biragyn, National Institute on aging) (
      • Baatar D.
      • Olkhanud P.
      • Newton D.
      • Sumitomo K.
      • Biragyn A.
      CCR4-expressing T cell tumors can be specifically controlled via delivery of toxins to chemokine receptors.
      ) for 3 days and then assessed for viability using a vital dye stain (arbitrary optical density units).
      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 E.
      • Russo G.
      • Cadoni S.
      • Narducci M.G.
      • Girardelli C.R.
      • De Pita O.
      • et al.
      Skewed expression of activation, differentiation and homing-related antigens in circulating cells from patients with cutaneous T cell lymphoma associated with CD7- T helper lymphocytes expansion.
      ). The downregulation 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 M.G.
      • Scala E.
      • Bresin A.
      • Caprini E.
      • Picchio M.C.
      • Remotti D.
      • et al.
      Skin homing of Sézary cells involves SDF-1-CXCR4 signaling and down-regulation of CD26/dipeptidylpeptidase IV.
      ), 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 that 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 of CCR4 that induce antibody-dependent cellular cytotoxicity have already been reported (
      • Ishida T.
      • Iida S.
      • Akatsuka Y.
      • Ishii T.
      • Miyazaki M.
      • Komatsu H.
      • et al.
      The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma.
      ;
      • Yano H.
      • Ishida T.
      • Inagaki A.
      • Ishii T.
      • Ding J.
      • Kusumoto S.
      • et al.
      Defucosylated anti CC chemokine receptor 4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/refractory Mycosis fungoides and Sézary syndrome.
      ). Furthermore, Richardson et al. reported that bexarotene downregulates CCR4 expression and/or function, suggesting another mechanism by which bexarotene is effective in CTCL (
      • Richardson S.K.
      • Newton S.B.
      • Bach T.L.
      • Budgin J.B.
      • Benoit B.M.
      • Lin J.H.
      • et al.
      Bexarotene blunts malignant T-cell chemotaxis in Sézary syndrome: reduction of chemokine receptor 4-positive lymphocytes and decreased chemotaxis to thymus and activation-regulated chemokine.
      ). 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 (Figure 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 D.
      • Olkhanud P.
      • Newton D.
      • Sumitomo K.
      • Biragyn A.
      CCR4-expressing T cell tumors can be specifically controlled via delivery of toxins to chemokine receptors.
      ) 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 an SS patient by CCL17-PE38 is shown in Figure 3b.

      Conclusions

      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 antireceptor antibodies as novel therapeutic agents.

      Conflict of Interest

      The authors declare no conflict of interest.

      ACKNOWLEDGMENTS

      Anke S. Lonsdorf is a recipient of an NIH-German Research Foundation (DFG) Career Transition Award.

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