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Chemokines and cutaneous lymphoma
Journal of Dermatological Science 59 (2010) 81–85
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Journal of Dermatological Science journal homepage: www.elsevier.com/jds
Invited review article
Chemokines and cutaneous lymphoma Makoto Sugaya * Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 April 2010 Accepted 15 May 2010
Chemokines are small molecules of 8–10 kDa that induce chemotaxis and activation of certain subsets of leukocytes. It has been recently shown that chemokines have broader function such as inhibition of apoptosis of target cells. The expression patterns of chemokines and chemokine receptors are specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organspecific human diseases. Primary cutaneous lymphomas are characterized by proliferation of clonally expanded lymphocytes in skin, but without detectable systemic involvement at the first diagnosis. Many chemokines are reported to be expressed in lesional skin of cutaneous lymphoma. Moreover, tumor cells of a certain group of cutaneous lymphoma express limited numbers of chemokine receptors, suggesting that interactions between chemokines and their receptors may explain skin-tropism of these types of lymphoma. This article focuses on chemokines expressed in lesional skin of cutaneous lymphoma and discusses their possible roles in disease progression.
Keywords: Chemokines Cutaneous lymphoma CXCL13 CCL17 CCL27 CCL26
ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
3. 4.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CXCL13 and B cell infiltration . . . . . . . . . . . . . . . . . . . 2.1. CXCL13 and lymphoid follicular formation . . . 2.2. CXCL13+ T cell lymphoma . . . . . . . . . . . . . . . . CXCL9, CXCL10 and epidermotropism . . . . . . . . . . . . CCL17, CCL27 and disease activity of MF/SS. . . . . . . . 4.1. Serum levels of CCL17 in patients with MF/SS 4.2. Serum levels of CCL27 in patients with MF/SS 4.3. CCR4 and CCR10 expression on tumor cells of CCL11, CCL26 and Th2 environment . . . . . . . . . . . . . . 5.1. CCR3 expression on tumor cells of ALCL . . . . . 5.2. CCL11, CCL26 and Th2 environment in MF/SS. Other chemokines in cutaneous lymphoma . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
...... ...... ...... ...... ...... ...... ...... ...... MF/SS. ...... ...... ...... ...... ...... ...... ......
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1. Introduction Chemokines are small molecules of 8–10 kDa that induce chemotaxis and activation of certain subsets of leukocytes. Structurally, they are classified into four types: CC chemokines, CXC chemokines, C chemokine, and CX3C chemokine, which is based on the pattern of cysteine residues in each protein [1]. It has
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been recently shown that chemokines have broader functions than just chemotaxis, such as inhibition of apoptosis of target cells [1,2]. The expression pattern of chemokines and chemokine receptors is specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases. For example, CCL17, also called thymus and activationregulated chemokine (TARC), is reported to be involved in various kinds of skin diseases [3]. There are many histologic types of malignant lymphoma, some of which preferentially affect specific organs. Primary cutaneous lymphomas are part of the spectrum of extranodal non-Hodgkin
0923-1811/$36.00 ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2010.05.005
M. Sugaya / Journal of Dermatological Science 59 (2010) 81–85
82 Table 1 Chemokines associated with cutaneous lymphoma. Chemokine
Receptors
Possible functions
References
CXCL13 CXCL9, 10 CCL17 CCL27 CCL11, 26
CXCR5 CXCR3 CCR4 CCR10 CCR3
CCL21
CCR7
[22,24,25] [5–10,29] [9–11,13,14,31] [12–14,35] [41] [48] [7,13,14]
CXCL12
CXCR4
Skin infiltration of B cells Epidermotropism of tumor cells Skin infiltration of tumor cells Skin infiltration of tumor cells Autocrine for ALCL Maintenance of Th2 environment Lymph node infiltration of tumor cells Skin infiltration of tumor cells
follicular formation such as Kimura’s disease. Taken together, CXCL13 expressed by FDCs induces chemotaxis of B cells, playing important roles in lymphoid follicular formation in skin (Fig. 1). Skin resident cells, such as keratinocytes, fibroblasts, or endothelial cells, do not express this chemokine, accounting for the rare infiltration of B cells into the skin. 2.2. CXCL13+ T cell lymphoma
2. CXCL13 and B cell infiltration
CXCL13 is expressed by TFHs as well as FDCs [18,19]. In angioimmunoblastic T cell lymphoma, malignant CD10+CXCL13+ T cells proliferate in involved lymph nodes, suggesting this type of lymphoma originates from TFHs [23]. Subsequent development of B cell lymphoma commonly occurs following the diagnosis of angioimmunoblastic T cell lymphoma [4]. Recently, primary cutaneous CD4+ small/medium T-cell lymphoma was reported to express markers of TFHs such as CXCL13, BCL-6, and PD-1 [24]. Infiltration of B cells in lesional skin is frequently seen in this type of lymphoma [4]. Interestingly, we and others have seen some cases of primary cutaneous T cell lymphoma, not otherwise specified, whose tumor cells were positive for CXCL13 [25]. B cell infiltration was remarkable in these cases and some of the patients subsequently developed diffuse large B cell lymphoma. Therefore, T cell lymphoma expressing CXCL13 is usually accompanied by massive B cell infiltration and may have a high risk of developing secondary B cell lymphoma.
2.1. CXCL13 and lymphoid follicular formation
3. CXCL9, CXCL10 and epidermotropism
CXCL13, also called B lymphocyte chemoattractant (BLC), is constitutively expressed within secondary lymphoid organs, regulating homing of B lymphocytes [16,17]. CXCL13 is a ligand for CXCR5, which is mainly expressed on B cells [17]. CXCL13 is mainly expressed by follicular DCs (FDCs) and follicular helper T cells (TFHs) [18,19]. Expression of CXCL13 was shown in lymphoproliferative disorders such as gastric mucosa-associated lymphoid tissue lymphoma and central nervous system lymphoma [20,21]. Our group has shown that CXCL13 is expressed within follicular structures of Kimura’s disease and pseudolymphoma with prominent follicular formation similar to reactive lymph nodes [22]. In primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, CXCL13 is also expressed. There is no expression of CXCL13 in MF/SS, lichen planus, and some cases of pseudolymphoma in which follicular formation was inconspicuous. As a source of CXCL13, CD21+ FDCs are detected in lymphoid follicles of reactive lymph nodes and skin specimens with prominent
CXCL9, also called monokine induced by interferon-g (Mig), and CXCL10, also called interferon-inducible protein-10 (IP-10), are ligands of CXCR3 and are chemoattractants for activated T cells [26]. Both chemokines are induced by the T helper (Th)1 cytokine IFN-g. Various types of cells and tissues express these chemokines, including keratinocytes and Langerhans cells [27,28]. MF has a classically prolonged clinical course that progresses over years through patch, plaque, and tumor stages, followed by lymph node and visceral involvement. CXCL9 and CXCL10 are expressed in lesional skin of MF in the patch and plaque stages, when epidermotropism of tumor cells is remarkable [5,29]. In addition, most infiltrating cells in the epidermis and some in the upper dermis express their receptor, CXCR3 [5–10]. Atypical lymphoid cells in tumor stage MF tend to express CCR4 rather than CXCR3 [9–11], suggesting that interactions between CXCL9, CXCL10 and CXCR3 are important for epidermotropism only in early stages of MF (Fig. 2).
[7,15]
lymphoma and are characterized by proliferation of clonally expanded lymphocytes in skin, but without detectable systemic involvement at the first diagnosis [4]. The most popular type of cutaneous malignant lymphoma is T cell lymphoma, including mycosis fungoides (MF) and Sezary syndrome (SS). Tumor cells of MF/SS express limited numbers of chemokine receptors, which suggests that interactions between chemokines and their receptors are involved in development of MF/SS [5–15]. This article focuses on chemokines expressed in lesional skin of cutaneous lymphoma and discusses their possible involvement in disease progression (Table 1).
[(Fig._1)TD$IG]
[(Fig._2)TD$IG]
Fig. 1. CXCL13 expression by follicular dendritic cells (FDCs) and follicular helper T cells (TFHs), inducing chemotaxis of B cells into cutaneous lymphoid follicles.
Fig. 2. Interaction between CXCL9, 10 and CXCR3, explaining epidermotropism at early stages of MF.
M. Sugaya / Journal of Dermatological Science 59 (2010) 81–85
4. CCL17, CCL27 and disease activity of MF/SS 4.1. Serum levels of CCL17 in patients with MF/SS To estimate disease activity of MF, the thickness of the cutaneous infiltrate or serum lactate dehydrogenase (LDH) levels or soluble interleukin 2 receptor (sIL-2R) levels are available. CCL17, also called thymus and activation-regulated chemokine (TARC), is a member of the CC chemokine family. It is a ligand of CCR4 and CCR8, and serves to recruit cells expressing these chemokine receptors [30]. CCL17 and CCR4 play important roles in the pathogenesis of inflammatory skin diseases such as atopic dermatitis [3]. We have reported that serum levels of CCL17 are elevated in patients with MF compared with normal healthy controls [10]. Serum levels of CCL17 in patients with tumor stage MF are much higher than those in patients in patch and plaque stages. Serum CCL17 levels strongly correlated with serum LDH and sIL-2R levels, both of which reflect MF disease activity [10,31]. 4.2. Serum levels of CCL27 in patients with MF/SS CCL27, also called cutaneous T cell-attracting chemokine (CTACK), belongs to the CC chemokine family and is a ligand for CCR10. It is selectively and constitutively produced in skin by epidermal keratinocytes [32] but is also detected on the surface of dermal endothelial cells [33]. CCL27 selectively attracts cutaneous lymphocyte antigen-positive, CCR10-positive memory T cells into inflammatory sites [32]. Serum CCL27 levels are elevated in various skin diseases such as atopic dermatitis and psoriasis [34]. We and others have reported that serum CCL27 levels of patients with MF/ SS are significantly higher than those of controls [12,35]. The levels of patients with tumor stage MF are significantly higher than those of patients in patch and plaque stages. Lastly, serum CCL27 levels are significantly correlated with tumor burden index, and with serum sIL-2R levels. 4.3. CCR4 and CCR10 expression on tumor cells of MF/SS Chemokine expression on tumor cells in MF differs according to disease stage. Most infiltrating cells in lesional skin of MF in patch and plaque stages express CXCR3 (Fig. 2) [5–10]. Tumor cells are less epidermotropic and transform into much larger cells in tumor stage MF. We and others have shown that these transformed large cells express CCR4 [9–11]. Circulating tumor cells as well as skininfiltrating cells in SS also express CCR4 [9,11,13,14]. CCL17 is expressed by keratinocytes and endothelial cells in lesional skin of
[(Fig._3)TD$IG]
Fig. 3. CCL17–CCR4 and CCL27–CCR10 interactions in the progression of MF/SS.
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MF/SS [10,11], suggesting important roles of CCL17–CCR4 interaction in disease progression of MF/SS (Fig. 3). Tumor cells in anaplastic large cell lymphoma and adult T cell lymphoma (ATL) also express CCR4 [36,37]. Thus, CCR4 expression on tumor cells in cutaneous T cell lymphoma (CTCL) may suggest poor prognosis. CCL27–CCR10 interactions are regarded to be most important for skin-homing of T cells [32]. It has been shown that CCR10 is expressed on tumor cells of MF/SS [12–14]. Keratinocytes in lesional skin of MF/SS express CCL27 much higher than those from normal skin [12]. Therefore, CCR10 expression on tumor cells of MF/SS may explain their preferential migration to and retention within skin (Fig. 3). 5. CCL11, CCL26 and Th2 environment 5.1. CCR3 expression on tumor cells of ALCL CCL11, also called eotaxin-1, belongs to the CC chemokine family and has potent chemotactic activity for CCR3+ cells such as eosinophils [38] as well as subpopulations of Th2 cells [39]. CCL11 was reported to be expressed by fibroblasts, endothelial cells, and tumor cells of primary cutaneous anaplastic large cell lymphoma (ALCL) [40]. CCR3, a sole receptor for CCL11, is expressed on atypical lymphoid cells of ALCL, but not on tumor cells of MF/SS [7,36,40]. Therefore, CCL11 may act in autocrine manner in primary cutaneous ALCL. 5.2. CCL11, CCL26 and Th2 environment in MF/SS CCL11 and CCL26, also called eotaxin-3, play important roles in allergic diseases such as atopic dermatitis and allergic asthma [41,42]. In Hodgkin lymphoma, CCL11 mRNA is upregulated within lesional tissues [43]. CCL11 was strongly expressed in fibroblasts of Hodgkin lymphoma [44]. CCR3, a receptor for CCL11 and CCL26, is expressed on eosinophils and subpopulations of Th2 cells [38,39]. CCL11 secreted by fibroblasts may play important roles in attracting Th2 cells and eosinophils into tissue, thus making a Th2-dominant microenvironment (Fig. 4). Patients with MF/SS frequently show eosinophilia and high levels of serum IgE. Th2 cytokine mRNA is detected in skin of patients with MF/SS [45]. Clonal T cells in SS transcribe and secrete mainly Th2 cytokines [46]. It is postulated that a Th2-dominant environment is beneficial for tumor cells by counter-regulating IFN-g-producing Th1 cells, which augment antitumor immune responses. Indeed, gene therapy approaches using adenoviruses encoding for IFN-g have been successfully used in CTCL [47].
[(Fig._4)TD$IG]
Fig. 4. CCL11 and CCL26 expression by surrounding fibroblasts, regulating Th2dominant tumor microenvironment in Hodgkin lymphoma and MF/SS.
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We have recently found that lesional skin of MF/SS at tumor or erythroderma stages contains significantly higher levels of CCL26 and CCR3 mRNA, compared to early stages of MF/SS [48]. Keratinocytes, endothelial cells, and dermal fibroblasts in lesional skin show stronger expression of CCL26 than normal skin. Moreover, both serum CCL11 and CCL26 levels of patients with MF/SS at advanced stages are significantly higher than healthy individuals. The concentrations of these chemokines correlated with serum sIL-2R levels. These results suggest that CCL11, CCL26 and CCR3 interactions promote a Th2-dominant tumor environment, which is closely correlated with development of MF/SS. This situation is quite similar to the Th2-dominant tumor environment that occurs in Hodgkin lymphoma (Fig. 4). 6. Other chemokines in cutaneous lymphoma SS is characterized by erythroderma, tumor cells in the peripheral blood, and lymphadenopathy. Tumor cells of Sezary cells express CCR7 [13,14], which is the key receptor for leukocytes to emigrate into lymph nodes. CCR7 is also reported to be expressed by tumor cells in some cases of MF at tumor stage [7]. Therefore, CCR7 expression may suggest a higher risk of tumor invasion to lymph nodes in MF/SS. Tumor cells of MF/SS are also reported to express CXCR4, a receptor for CXCL12 [7,15]. CXCL12, which is abundantly produced in skin, could play a role in skin-homing of tumor cells of SS through the regulatory activity of CD26 [15]. 7. Conclusion Many chemokines are involved in the development of cutaneous lymphoma as discussed in this manuscript. Secondary B cell infiltration, epidermotropism, skin-homing, and lymph node invasion of tumor cells can be explained by expression patterns of chemokines and chemokine receptors. Biologics targeting chemokines and their receptors are promising strategies for cutaneous lymphoma that are resistant to the current therapy. Indeed, humanized defucosylated anti-CCR4 monoclonal antibody showed potent antitumor activity mediated by highly enhanced antibody-dependent cellular cytotoxicity against primary ATL cells both in vitro and ex vivo [49]. Efficacy of anti-CCR4 monoclonal antibodies for ATL is currently being assessed in clinical trials. Acknowledgements The author is grateful to Dr. T. Kakinuma, Dr. H. Ohmatsu, Dr. S. Kagami, and Dr. T Miyagaki for their contributions to the research. The author also thanks Dr. Andrew Blauvelt (Department of Dermatology, Oregon Health & Science University) for many helpful comments. The study was supported by grants from the Ministry of Education, Culture, Sports and Technology in Japan. References [1] Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006;354:610–21. [2] Murakami T, Cardones AR, Finkelstein SE, Restifo NP, Klaunberg BA, Nestle FO, et al. Immune evasion by murine melanoma mediated through CC chemokine receptor-10. J Exp Med 2003;198:1337–47. [3] Saeki H, Tamaki K. Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases. J Dermatol Sci 2006;43:75–84. [4] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. [5] Sarris AH, Esgleyes-Ribot T, Crow M, Broxmeyer HE, Karasavvas N, Pugh W, et al. Cytokine loops involving interferon-gamma and IP-10, a cytokine chemotactic for CD4+ lymphocytes: an explanation for the epidermotropism of cutaneous T-cell lymphoma? Blood 1995;86:651–8.
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chemokine, macrophage-derived chemokine, and I-309. J Immunol 2000;164: 4048–54. Masui Y, Sugaya M, Kagami S, Fujita H, Yano S, Nagao M, et al. Se´zary syndrome treated with narrowband ultraviolet B: time-course measurement of serum levels of CCL17/CCL27. Clin Exp Dermatol 2007;32:57–9. Morales J, Homey B, Vicari AP, Hudak S, Oldham E, Hedrick J, et al. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci USA 1999;96:14470–5. Homey B, Alenius H, Mu¨ller A, Soto H, Bowman EP, Yuan W, et al. CCL27-CCR10 interactions regulate T cell-mediated skin inflammation. Nat Med 2002;8: 157–65. Kakinuma T, Saeki H, Tsunemi Y, Fujita H, Asano N, Mitsui H, et al. Increased serum cutaneous T cell-attracting chemokine (CCL27) levels in patients with atopic dermatitis and psoriasis vulgaris. J Allergy Clin Immunol 2003;111: 592–7. Kagami S, Sugaya M, Minatani Y, Ohmatsu H, Kakinuma T, Fujita H, et al. Elevated serum CTACK/CCL27 levels in C.T.C.L. J Invest Dermatol 2006;126: 1189–91. Yamaguchi T, Ohshima K, Karube K, Kawano R, Nakayama J, Suzumiya J, et al. Expression of chemokines and chemokine receptors in cutaneous CD30+ lymphoproliferative disorders. Br J Dermatol 2006;154:904–9. Yoshie O, Fujisawa R, Nakayama T, Harasawa H, Tago H, Izawa D, et al. Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. Blood 2002;99:1505–11. Forssmann U, Uguccioni M, Loetscher P, Dahinden CA, Langen H, Thelen M, et al. Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. J Exp Med 1997;185:2171–6. Sallusto F, Mackay CR, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 1997;277:2005–7. Kleinhans M, Tun-Kyi A, Gilliet M, Kadin ME, Dummer R, Burg G, et al. Functional expression of the eotaxin receptor CCR3 in CD30+ cutaneous Tcell lymphoma. Blood 2003;101:1487–93. Berkman N, Ohnona S, Chung FK, Breuer R. Eotaxin-3 but not eotaxin gene expression is upregulated in asthmatics 24 hours after allergen challenge. Am J Respir Cell Mol Biol 2001;24:682–7. Kagami S, Kakinuma T, Saeki H, Tsunemi Y, Fujita H, Nakamura K, et al. Significant elevation of serum levels of eotaxin-3, but not of eotaxin-2/ CCL24, in patients with atopic dermatitis: serum eotaxin-3 levels reflect the disease activity of atopic dermatitis. Clin Exp Immunol 2003; 134:309–13.
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[43] Teruya-Feldstein J, Jaffe ES, Burd PR, Kingma DW, Setsuda JE, Tosato G. Differential chemokine expression in tissues involved by Hodgkin’s disease: direct correlation of eotaxin expression and tissue eosinophilia. Blood 1999; 93:2463–70. [44] Jundt F, Anagnostopoulos I, Bommert K, Emmerich F, Mu¨ller G, Foss HD, et al. Hodgkin/Reed–Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. Blood 1999;94:2065–71. [45] Vowels BR, Lessin SR, Cassin M, Jaworsky C, Benoit B, Wolfe JT, et al. Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma. J Invest Dermatol 1994;103:669–73. [46] Dummer R, Heald PW, Nestle FO, Ludwig E, Laine E, Hemmi S, et al. Se´zary syndrome T-cell clones display T-helper 2 cytokines and express the accessory factor-1 (interferon-gamma receptor beta-chain). Blood 1996;88:1383–9. [47] Urosevic M, Fujii K, Calmels B, Laine E, Kobert N, Acres B, et al. Type I IFN innate immune response to adenovirus-mediated IFN-gamma gene transfer contributes to the regression of cutaneous lymphomas. J Clin Invest 2007;117:2834– 46. [48] Miyagaki T, Sugaya M, Fujita H, Ohmatsu H, Kakinuma T, Kadono T, et al. Eotaxins and CCR3 interaction regulates Th2 environment of cutaneous T cell lymphoma. J Invest Dermatol, 2010 May 27. [Epub ahead of print], doi:10.1038/jid.2010.128. [49] Ishii T, Ishida T, Utsunomiya A, Inagaki A, Yano H, Komatsu H, et al. Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. Clin Cancer Res 2010;16:1520–31. Makoto Sugaya was graduated from University of Tokyo and received his MD degree in 1995. He received his PhD in dermatology at University of Tokyo in 2001. He studied virology and immunology under the supervision of Dr. Andrew Blauvelt at the Dermatology Branch, National Cancer Institute, National Institute of Health in Bethesda, MD. While there, he worked on pathogenesis of HIV disease, with an emphasis on infection of Langerhans cells and pathogenesis of Kaposi’s sarcoma. Since 2007, he has been an assistant professor in Department of Dermatology, University of Tokyo. His research interests include cutaneous immunology, chemokines, and malignant lymphoma. He has been the only Asian board member of International Society for Cutaneous Lymphoma since 2007.
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Journal of Dermatological Science journal homepage: www.elsevier.com/jds
Invited review article
Chemokines and cutaneous lymphoma Makoto Sugaya * Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 13 April 2010 Accepted 15 May 2010
Chemokines are small molecules of 8–10 kDa that induce chemotaxis and activation of certain subsets of leukocytes. It has been recently shown that chemokines have broader function such as inhibition of apoptosis of target cells. The expression patterns of chemokines and chemokine receptors are specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organspecific human diseases. Primary cutaneous lymphomas are characterized by proliferation of clonally expanded lymphocytes in skin, but without detectable systemic involvement at the first diagnosis. Many chemokines are reported to be expressed in lesional skin of cutaneous lymphoma. Moreover, tumor cells of a certain group of cutaneous lymphoma express limited numbers of chemokine receptors, suggesting that interactions between chemokines and their receptors may explain skin-tropism of these types of lymphoma. This article focuses on chemokines expressed in lesional skin of cutaneous lymphoma and discusses their possible roles in disease progression.
Keywords: Chemokines Cutaneous lymphoma CXCL13 CCL17 CCL27 CCL26
ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CXCL13 and B cell infiltration . . . . . . . . . . . . . . . . . . . 2.1. CXCL13 and lymphoid follicular formation . . . 2.2. CXCL13+ T cell lymphoma . . . . . . . . . . . . . . . . CXCL9, CXCL10 and epidermotropism . . . . . . . . . . . . CCL17, CCL27 and disease activity of MF/SS. . . . . . . . 4.1. Serum levels of CCL17 in patients with MF/SS 4.2. Serum levels of CCL27 in patients with MF/SS 4.3. CCR4 and CCR10 expression on tumor cells of CCL11, CCL26 and Th2 environment . . . . . . . . . . . . . . 5.1. CCR3 expression on tumor cells of ALCL . . . . . 5.2. CCL11, CCL26 and Th2 environment in MF/SS. Other chemokines in cutaneous lymphoma . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Chemokines are small molecules of 8–10 kDa that induce chemotaxis and activation of certain subsets of leukocytes. Structurally, they are classified into four types: CC chemokines, CXC chemokines, C chemokine, and CX3C chemokine, which is based on the pattern of cysteine residues in each protein [1]. It has
* Tel.: +81 3 5800 8661; fax: +81 3 3814 1503. E-mail address: [email protected].
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been recently shown that chemokines have broader functions than just chemotaxis, such as inhibition of apoptosis of target cells [1,2]. The expression pattern of chemokines and chemokine receptors is specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases. For example, CCL17, also called thymus and activationregulated chemokine (TARC), is reported to be involved in various kinds of skin diseases [3]. There are many histologic types of malignant lymphoma, some of which preferentially affect specific organs. Primary cutaneous lymphomas are part of the spectrum of extranodal non-Hodgkin
0923-1811/$36.00 ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2010.05.005
M. Sugaya / Journal of Dermatological Science 59 (2010) 81–85
82 Table 1 Chemokines associated with cutaneous lymphoma. Chemokine
Receptors
Possible functions
References
CXCL13 CXCL9, 10 CCL17 CCL27 CCL11, 26
CXCR5 CXCR3 CCR4 CCR10 CCR3
CCL21
CCR7
[22,24,25] [5–10,29] [9–11,13,14,31] [12–14,35] [41] [48] [7,13,14]
CXCL12
CXCR4
Skin infiltration of B cells Epidermotropism of tumor cells Skin infiltration of tumor cells Skin infiltration of tumor cells Autocrine for ALCL Maintenance of Th2 environment Lymph node infiltration of tumor cells Skin infiltration of tumor cells
follicular formation such as Kimura’s disease. Taken together, CXCL13 expressed by FDCs induces chemotaxis of B cells, playing important roles in lymphoid follicular formation in skin (Fig. 1). Skin resident cells, such as keratinocytes, fibroblasts, or endothelial cells, do not express this chemokine, accounting for the rare infiltration of B cells into the skin. 2.2. CXCL13+ T cell lymphoma
2. CXCL13 and B cell infiltration
CXCL13 is expressed by TFHs as well as FDCs [18,19]. In angioimmunoblastic T cell lymphoma, malignant CD10+CXCL13+ T cells proliferate in involved lymph nodes, suggesting this type of lymphoma originates from TFHs [23]. Subsequent development of B cell lymphoma commonly occurs following the diagnosis of angioimmunoblastic T cell lymphoma [4]. Recently, primary cutaneous CD4+ small/medium T-cell lymphoma was reported to express markers of TFHs such as CXCL13, BCL-6, and PD-1 [24]. Infiltration of B cells in lesional skin is frequently seen in this type of lymphoma [4]. Interestingly, we and others have seen some cases of primary cutaneous T cell lymphoma, not otherwise specified, whose tumor cells were positive for CXCL13 [25]. B cell infiltration was remarkable in these cases and some of the patients subsequently developed diffuse large B cell lymphoma. Therefore, T cell lymphoma expressing CXCL13 is usually accompanied by massive B cell infiltration and may have a high risk of developing secondary B cell lymphoma.
2.1. CXCL13 and lymphoid follicular formation
3. CXCL9, CXCL10 and epidermotropism
CXCL13, also called B lymphocyte chemoattractant (BLC), is constitutively expressed within secondary lymphoid organs, regulating homing of B lymphocytes [16,17]. CXCL13 is a ligand for CXCR5, which is mainly expressed on B cells [17]. CXCL13 is mainly expressed by follicular DCs (FDCs) and follicular helper T cells (TFHs) [18,19]. Expression of CXCL13 was shown in lymphoproliferative disorders such as gastric mucosa-associated lymphoid tissue lymphoma and central nervous system lymphoma [20,21]. Our group has shown that CXCL13 is expressed within follicular structures of Kimura’s disease and pseudolymphoma with prominent follicular formation similar to reactive lymph nodes [22]. In primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, CXCL13 is also expressed. There is no expression of CXCL13 in MF/SS, lichen planus, and some cases of pseudolymphoma in which follicular formation was inconspicuous. As a source of CXCL13, CD21+ FDCs are detected in lymphoid follicles of reactive lymph nodes and skin specimens with prominent
CXCL9, also called monokine induced by interferon-g (Mig), and CXCL10, also called interferon-inducible protein-10 (IP-10), are ligands of CXCR3 and are chemoattractants for activated T cells [26]. Both chemokines are induced by the T helper (Th)1 cytokine IFN-g. Various types of cells and tissues express these chemokines, including keratinocytes and Langerhans cells [27,28]. MF has a classically prolonged clinical course that progresses over years through patch, plaque, and tumor stages, followed by lymph node and visceral involvement. CXCL9 and CXCL10 are expressed in lesional skin of MF in the patch and plaque stages, when epidermotropism of tumor cells is remarkable [5,29]. In addition, most infiltrating cells in the epidermis and some in the upper dermis express their receptor, CXCR3 [5–10]. Atypical lymphoid cells in tumor stage MF tend to express CCR4 rather than CXCR3 [9–11], suggesting that interactions between CXCL9, CXCL10 and CXCR3 are important for epidermotropism only in early stages of MF (Fig. 2).
[7,15]
lymphoma and are characterized by proliferation of clonally expanded lymphocytes in skin, but without detectable systemic involvement at the first diagnosis [4]. The most popular type of cutaneous malignant lymphoma is T cell lymphoma, including mycosis fungoides (MF) and Sezary syndrome (SS). Tumor cells of MF/SS express limited numbers of chemokine receptors, which suggests that interactions between chemokines and their receptors are involved in development of MF/SS [5–15]. This article focuses on chemokines expressed in lesional skin of cutaneous lymphoma and discusses their possible involvement in disease progression (Table 1).
[(Fig._1)TD$IG]
[(Fig._2)TD$IG]
Fig. 1. CXCL13 expression by follicular dendritic cells (FDCs) and follicular helper T cells (TFHs), inducing chemotaxis of B cells into cutaneous lymphoid follicles.
Fig. 2. Interaction between CXCL9, 10 and CXCR3, explaining epidermotropism at early stages of MF.
M. Sugaya / Journal of Dermatological Science 59 (2010) 81–85
4. CCL17, CCL27 and disease activity of MF/SS 4.1. Serum levels of CCL17 in patients with MF/SS To estimate disease activity of MF, the thickness of the cutaneous infiltrate or serum lactate dehydrogenase (LDH) levels or soluble interleukin 2 receptor (sIL-2R) levels are available. CCL17, also called thymus and activation-regulated chemokine (TARC), is a member of the CC chemokine family. It is a ligand of CCR4 and CCR8, and serves to recruit cells expressing these chemokine receptors [30]. CCL17 and CCR4 play important roles in the pathogenesis of inflammatory skin diseases such as atopic dermatitis [3]. We have reported that serum levels of CCL17 are elevated in patients with MF compared with normal healthy controls [10]. Serum levels of CCL17 in patients with tumor stage MF are much higher than those in patients in patch and plaque stages. Serum CCL17 levels strongly correlated with serum LDH and sIL-2R levels, both of which reflect MF disease activity [10,31]. 4.2. Serum levels of CCL27 in patients with MF/SS CCL27, also called cutaneous T cell-attracting chemokine (CTACK), belongs to the CC chemokine family and is a ligand for CCR10. It is selectively and constitutively produced in skin by epidermal keratinocytes [32] but is also detected on the surface of dermal endothelial cells [33]. CCL27 selectively attracts cutaneous lymphocyte antigen-positive, CCR10-positive memory T cells into inflammatory sites [32]. Serum CCL27 levels are elevated in various skin diseases such as atopic dermatitis and psoriasis [34]. We and others have reported that serum CCL27 levels of patients with MF/ SS are significantly higher than those of controls [12,35]. The levels of patients with tumor stage MF are significantly higher than those of patients in patch and plaque stages. Lastly, serum CCL27 levels are significantly correlated with tumor burden index, and with serum sIL-2R levels. 4.3. CCR4 and CCR10 expression on tumor cells of MF/SS Chemokine expression on tumor cells in MF differs according to disease stage. Most infiltrating cells in lesional skin of MF in patch and plaque stages express CXCR3 (Fig. 2) [5–10]. Tumor cells are less epidermotropic and transform into much larger cells in tumor stage MF. We and others have shown that these transformed large cells express CCR4 [9–11]. Circulating tumor cells as well as skininfiltrating cells in SS also express CCR4 [9,11,13,14]. CCL17 is expressed by keratinocytes and endothelial cells in lesional skin of
[(Fig._3)TD$IG]
Fig. 3. CCL17–CCR4 and CCL27–CCR10 interactions in the progression of MF/SS.
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MF/SS [10,11], suggesting important roles of CCL17–CCR4 interaction in disease progression of MF/SS (Fig. 3). Tumor cells in anaplastic large cell lymphoma and adult T cell lymphoma (ATL) also express CCR4 [36,37]. Thus, CCR4 expression on tumor cells in cutaneous T cell lymphoma (CTCL) may suggest poor prognosis. CCL27–CCR10 interactions are regarded to be most important for skin-homing of T cells [32]. It has been shown that CCR10 is expressed on tumor cells of MF/SS [12–14]. Keratinocytes in lesional skin of MF/SS express CCL27 much higher than those from normal skin [12]. Therefore, CCR10 expression on tumor cells of MF/SS may explain their preferential migration to and retention within skin (Fig. 3). 5. CCL11, CCL26 and Th2 environment 5.1. CCR3 expression on tumor cells of ALCL CCL11, also called eotaxin-1, belongs to the CC chemokine family and has potent chemotactic activity for CCR3+ cells such as eosinophils [38] as well as subpopulations of Th2 cells [39]. CCL11 was reported to be expressed by fibroblasts, endothelial cells, and tumor cells of primary cutaneous anaplastic large cell lymphoma (ALCL) [40]. CCR3, a sole receptor for CCL11, is expressed on atypical lymphoid cells of ALCL, but not on tumor cells of MF/SS [7,36,40]. Therefore, CCL11 may act in autocrine manner in primary cutaneous ALCL. 5.2. CCL11, CCL26 and Th2 environment in MF/SS CCL11 and CCL26, also called eotaxin-3, play important roles in allergic diseases such as atopic dermatitis and allergic asthma [41,42]. In Hodgkin lymphoma, CCL11 mRNA is upregulated within lesional tissues [43]. CCL11 was strongly expressed in fibroblasts of Hodgkin lymphoma [44]. CCR3, a receptor for CCL11 and CCL26, is expressed on eosinophils and subpopulations of Th2 cells [38,39]. CCL11 secreted by fibroblasts may play important roles in attracting Th2 cells and eosinophils into tissue, thus making a Th2-dominant microenvironment (Fig. 4). Patients with MF/SS frequently show eosinophilia and high levels of serum IgE. Th2 cytokine mRNA is detected in skin of patients with MF/SS [45]. Clonal T cells in SS transcribe and secrete mainly Th2 cytokines [46]. It is postulated that a Th2-dominant environment is beneficial for tumor cells by counter-regulating IFN-g-producing Th1 cells, which augment antitumor immune responses. Indeed, gene therapy approaches using adenoviruses encoding for IFN-g have been successfully used in CTCL [47].
[(Fig._4)TD$IG]
Fig. 4. CCL11 and CCL26 expression by surrounding fibroblasts, regulating Th2dominant tumor microenvironment in Hodgkin lymphoma and MF/SS.
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We have recently found that lesional skin of MF/SS at tumor or erythroderma stages contains significantly higher levels of CCL26 and CCR3 mRNA, compared to early stages of MF/SS [48]. Keratinocytes, endothelial cells, and dermal fibroblasts in lesional skin show stronger expression of CCL26 than normal skin. Moreover, both serum CCL11 and CCL26 levels of patients with MF/SS at advanced stages are significantly higher than healthy individuals. The concentrations of these chemokines correlated with serum sIL-2R levels. These results suggest that CCL11, CCL26 and CCR3 interactions promote a Th2-dominant tumor environment, which is closely correlated with development of MF/SS. This situation is quite similar to the Th2-dominant tumor environment that occurs in Hodgkin lymphoma (Fig. 4). 6. Other chemokines in cutaneous lymphoma SS is characterized by erythroderma, tumor cells in the peripheral blood, and lymphadenopathy. Tumor cells of Sezary cells express CCR7 [13,14], which is the key receptor for leukocytes to emigrate into lymph nodes. CCR7 is also reported to be expressed by tumor cells in some cases of MF at tumor stage [7]. Therefore, CCR7 expression may suggest a higher risk of tumor invasion to lymph nodes in MF/SS. Tumor cells of MF/SS are also reported to express CXCR4, a receptor for CXCL12 [7,15]. CXCL12, which is abundantly produced in skin, could play a role in skin-homing of tumor cells of SS through the regulatory activity of CD26 [15]. 7. Conclusion Many chemokines are involved in the development of cutaneous lymphoma as discussed in this manuscript. Secondary B cell infiltration, epidermotropism, skin-homing, and lymph node invasion of tumor cells can be explained by expression patterns of chemokines and chemokine receptors. Biologics targeting chemokines and their receptors are promising strategies for cutaneous lymphoma that are resistant to the current therapy. Indeed, humanized defucosylated anti-CCR4 monoclonal antibody showed potent antitumor activity mediated by highly enhanced antibody-dependent cellular cytotoxicity against primary ATL cells both in vitro and ex vivo [49]. Efficacy of anti-CCR4 monoclonal antibodies for ATL is currently being assessed in clinical trials. Acknowledgements The author is grateful to Dr. T. Kakinuma, Dr. H. Ohmatsu, Dr. S. Kagami, and Dr. T Miyagaki for their contributions to the research. The author also thanks Dr. Andrew Blauvelt (Department of Dermatology, Oregon Health & Science University) for many helpful comments. The study was supported by grants from the Ministry of Education, Culture, Sports and Technology in Japan. References [1] Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006;354:610–21. [2] Murakami T, Cardones AR, Finkelstein SE, Restifo NP, Klaunberg BA, Nestle FO, et al. Immune evasion by murine melanoma mediated through CC chemokine receptor-10. J Exp Med 2003;198:1337–47. [3] Saeki H, Tamaki K. Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases. J Dermatol Sci 2006;43:75–84. [4] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008. [5] Sarris AH, Esgleyes-Ribot T, Crow M, Broxmeyer HE, Karasavvas N, Pugh W, et al. Cytokine loops involving interferon-gamma and IP-10, a cytokine chemotactic for CD4+ lymphocytes: an explanation for the epidermotropism of cutaneous T-cell lymphoma? Blood 1995;86:651–8.
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