CCL17 explained

CCL17 is a powerful chemokine produced in the thymus and by antigen-presenting cells like dendritic cells, macrophages, and monocytes.^[1] CCL17 plays a complex role in cancer. It attracts T-regulatory cells allowing for some cancers to evade an immune response. However, in other cancers, such as melanoma, an increase in CCL17 is linked to an improved outcome. CCL17 has also been linked to autoimmune and allergic diseases.

Classification

CCL17 (CC chemokine ligand 17) was initially named TARC (thymus- and activation-regulated chemokine) when first isolated in 1996.^[2] It was later renamed CCL17 as the naming conventions for all cytokines were updated to standardize names.

Function

Cytokines, like CCL17, help cells communicate with one another, and stimulate cell movement. Chemokines are a type of cytokine that attract white blood cells to sites of inflammation or disease. CCL17 as well as its partner chemokine CCL22 induce chemotaxis in T-helper cells.^{[3] [4]} They do this by binding to CCR4, a chemokine receptor expressed on type 2 helper T cells, cutaneous lymphocyte skin-localizing T cells, and regulatory T cells.^[5] CCR4 is also expressed by T cells involved in adult T-cell leukemia/lymphoma and cutaneous T cell lymphomas, making its ligands (namely CCL17) an attractive target for novel therapies as described below. CCL17 is one of the few chemokines that are not stored in the body, except in the thymus; these chemokines are made when needed by dendritic cells, macrophages, and monocytes. CCL17 is expressed constitutively in the thymus, but only transiently in phytohemagglutinin-stimulated peripheral blood mononuclear cells. CCL17 can also be detected in other tissues such as the colon, small intestine, and lung. Granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulates CCL17 production in monocytes and macrophages.^[6] Dendritic cells will produce large quantities of CCL17 when stimulated with IL-4 or TSLP.^[7]

CCL17 was the first CC chemokine identified that interacted with T cells with high affinity. CCL17 was also found to interact with monocytes, but with less affinity. It does not interact with granulocytes. It acts as a powerful chemoattractant to T-helper cells and T-regulatory cells because both can express CCR4.^[8]

Cancer

Classic Hodgkin lymphoma

CCL17 was found to be highly expressed by the tumor cells of classic Hodgkin lymphoma.^[9] It can be detected by immunohistochemistry in >90% of cases in a diagnostic setting and is highly specific within B cell derived cancers.^[10] CCL17 is mainly responsible for the presence of large amounts of T-helper and T-regulatory cells in the tumor microenvironment, which is considered a hallmark of Hodgkin lymphoma.^[11] Levels of CCL17 in serum are ~400 times higher in Hodgkin lymphoma patients than in healthy controls and are strongly associated with tumor volume, disease stage, and response to therapy.^{[12] [13] [14] [15] [16] [17] [18] [19] [20]} Its levels are increasing already several years prior to symptoms and diagnosis in many Hodgkin lymphoma patients.^[21]

Solid cancers

This chemokine is very important in the human body’s response to cancers. While it sometimes allows cancer to invade more rapidly, it more often helps the human body fight cancer. Some cancers that form tumors, such as breast cancer, produce CCL17 which draws T regulatory cells into the area, enhancing the cancer’s ability to invade. On the other hand, CCL17 will also activate tumor-infiltrating lymphocytes tumors. For many cancers, the more CCL17 in the area, the better the prognosis is for cancer survival or recovery.

Inflammation

Like many cytokines, CCL17 is inflammatory, so while it plays a largely helpful role in attacking cancers, it can induce inflammatory diseases, including allergic skin diseases. Because of its inflammatory effects, much of the medical research is on methods to mitigate CCL17. Neutralizing CCL17 with monoclonal antibodies has been shown to relieve inflammatory arthritis and osteoarthritis. Topical steroids have been found to be an effective tool in normalizing levels of CCL17.

Autoimmunity

CCL17 is known to help leukocytes (and especially eosinophils) target their response to skin-located pathogens.^[22] This often occurs through the CCL17-CCR4 interaction on type 2 T helper cells, which then secrete a variety of interleukins. Direct interactions between CCL17 and eosinophils has been observed but not well defined. However, overexpressed CCL17 has been linked to atopic dermatitis (eczema) and multiple sclerosis, among other autoimmune diseases.^[23] Studies have shown that children with allergies and atopic dermatitis have higher quantiles of CCL17 compared to children without allergies. As such, therapeutic approaches involving CCL17 regulation have shown some success in several cases.^{[24] [25]} This intervention often involves interfering with CCR4 through monoclonal antibody treatment (such as mogamulizumab). Another option is small-molecule interaction with CCR4, which has not yet had any clinical success.

Atopic dermatitis (eczema)

Researchers have found that type 2 helper-T cells in lesions of atopic dermatitis (AD) express more IL-4 and IL-13 than unaffected Th2 cells. Dendritic cells respond to IL-4 and IL-13 by secreting CCL17 (as well as CCL18 and CCL22), especially in "barrier-disrupted" skin (such as lesional skin).^[26] Because CCL17 is a key attractant for Th2, this creates a cycle of Th2 recruitment, IL-4 and IL-13 signaling, dendritic cell secretion of CCL17, and further recruitment of Th2 cells. Severity of AD is therefore correlated with concentration of CCL17 and CCL22 in both the blood serum and interstitial fluid of pediatric and adult patients with either acute or chronic AD. Because Th2 cells are present at elevated levels during pregnancy, a buildup of CCL17 in umbilical cord blood may summon more Th2 cells, causing the aforementioned positive feedback loop. This is correlated with a higher likelihood of developing AD (and other allergic diseases) in infants (including for mothers without AD), especially for the first two years of infancy.

In adult patients, other signals (such as IL-22) have been shown to correlate with the severity and chronicity of AD in addition to levels of CCL17, although the causal relationships between each of these other signals and CCL17 are not all yet known. Other signaling components, like TSLP, are induced by other lesional epidermal cells and directly upregulate CCL17 production.

Clinically, CCL17 has recently shown promise as a useful biomarker for AD severity as well as efficacy of treatment.^{[27] [28]} Historically, physicians have used mostly visual, qualitative evaluations of lesion progress, but using CCL17 to quantify AD has allowed for more precise and accurate records of progress (or regression) during treatment. In concert with this, proposed treatments for AD include topical regulation of CCL17. Especially for infantile AD, where prolonged AD has been linked to severe food allergies, early quantification and treatment is especially important. This treatment may take the form of small-molecule inhibition of CCL17-CCR4 binding, which inhibits recruitment of Th2 cells and subsequent development of lesions.

Multiple sclerosis (and EAE)

Multiple sclerosis (MS) (and the animal model EAE) are autoimmune diseases characterized in part by changes in the expression and regulation of CCL17 in cerebrospinal fluid.^[29] There is also evidence to suggest that certain SNPs in the CCL17 and CCL22 genes may raise the risk of MS for an individual.

While type 2 helper T (Th2) cells are a key component of AD because they are localized to the skin through the CCL17-CCR4 interaction, memory Th17 cells seem to express high levels of CCR4 in both human and murine models of MS and are therefore likely candidates for study and therapy.

Treatments of MS (such as natalizumab or methylprednisolone) seem to lower overall chemokine levels (notably including either CCL17 itself or factors that are known to induce CCL17 production) in addition to other purported primary functions. However, these findings are complicated by CCR4 up- and downregulation findings, which have sometimes seemed counter to the CCL17 localization pathways. Experimental explorations with CCL17-deficient mice have therefore counterintuitively given different information than experiments measuring CCR4 regulation for EAE.   

Other disorders

Several other disorders are also correlated with high levels of CCL17 or use CCL17 to localize Th2 cells. CCL17 can act as an inflammatory agent or as a symptom, and in either case, disrupting or manipulating the expression or ligand binding offers a therapeutic target. And, regardless of therapeutic potential, it can be used as a biomarker of disease.

• Drug rash with eosinophilia and systemic symptoms (DRESS)
• Bullous pemphigoid (BP)
• Senile erythroderma
• Eosinophilic pustular folliculitis
• Chronic spontaneous urticaria (hives)
• Maculopapular exanthema
• Stevens-Johnson syndrome/toxic epidermal necrolysis
• (Non-)episodic angioedema with eosinophilia
• Allergic asthma
• Allergic rhinitis/chronic rhinosinusitis with nasal polyps (CRSwNP)
• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
• Acute and chronic eosinophilic pneumonia
• Mycosis fungoides (MF)
• Sezary syndrome (SS)
• Lymphocytic variant HES
• Acute disseminated encephalomyelitis (ADEM)^[30]
• Neuromyelitis optica (NMO) (Devic's disease)^[31]

Chromosomal location

In humans the gene for CCL17 is located on chromosome 16 along with other chemokines including CCL22 and CX3CL1.^{[32] [33]}

Further reading

• Saeki H, Tamaki K . Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases . Journal of Dermatological Science . 43 . 2 . 75–84 . August 2006 . 16859899 . 10.1016/j.jdermsci.2006.06.002 .
• Imai T, Yoshida T, Baba M, Nishimura M, Kakizaki M, Yoshie O . Molecular cloning of a novel T cell-directed CC chemokine expressed in thymus by signal sequence trap using Epstein-Barr virus vector . The Journal of Biological Chemistry . 271 . 35 . 21514–21521 . August 1996 . 8702936 . 10.1074/jbc.271.35.21514 . free .
• Nomiyama H, Imai T, Kusuda J, Miura R, Callen DF, Yoshie O . Assignment of the human CC chemokine gene TARC (SCYA17) to chromosome 16q13 . Genomics . 40 . 1 . 211–213 . February 1997 . 9070951 . 10.1006/geno.1996.4552 .
• Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O . The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4 . The Journal of Biological Chemistry . 272 . 23 . 15036–15042 . June 1997 . 9169480 . 10.1074/jbc.272.23.15036 . free .
• Imai T, Chantry D, Raport CJ, Wood CL, Nishimura M, Godiska R, Yoshie O, Gray PW . 6 . Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4 . The Journal of Biological Chemistry . 273 . 3 . 1764–1768 . January 1998 . 9430724 . 10.1074/jbc.273.3.1764 . free .
• Bernardini G, Hedrick J, Sozzani S, Luini W, Spinetti G, Weiss M, Menon S, Zlotnik A, Mantovani A, Santoni A, Napolitano M . 6 . Identification of the CC chemokines TARC and macrophage inflammatory protein-1 beta as novel functional ligands for the CCR8 receptor . European Journal of Immunology . 28 . 2 . 582–588 . February 1998 . 9521068 . 10.1002/(SICI)1521-4141(199802)28:02<582::AID-IMMU582>3.0.CO;2-A . free .
• Nomiyama H, Imai T, Kusuda J, Miura R, Callen DF, Yoshie O . Human chemokines fractalkine (SCYD1), MDC (SCYA22) and TARC (SCYA17) are clustered on chromosome 16q13 . Cytogenetics and Cell Genetics . 81 . 1 . 10–11 . 1998 . 9691168 . 10.1159/000015000 . 2024-07-29 . 46851784 .
• Struyf S, Proost P, Sozzani S, Mantovani A, Wuyts A, De Clercq E, Schols D, Van Damme J . 6 . Enhanced anti-HIV-1 activity and altered chemotactic potency of NH2-terminally processed macrophage-derived chemokine (MDC) imply an additional MDC receptor . Journal of Immunology . 161 . 6 . 2672–2675 . September 1998 . 10.4049/jimmunol.161.6.2672 . 9743322 . 25336802 . free .
• Loftus BJ, Kim UJ, Sneddon VP, Kalush F, Brandon R, Fuhrmann J, Mason T, Crosby ML, Barnstead M, Cronin L, Deslattes Mays A, Cao Y, Xu RX, Kang HL, Mitchell S, Eichler EE, Harris PC, Venter JC, Adams MD . 6 . Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q . Genomics . 60 . 3 . 295–308 . September 1999 . 10493829 . 10.1006/geno.1999.5927 .
• Garlisi CG, Xiao H, Tian F, Hedrick JA, Billah MM, Egan RW, Umland SP . The assignment of chemokine-chemokine receptor pairs: TARC and MIP-1 beta are not ligands for human CC-chemokine receptor 8 . European Journal of Immunology . 29 . 10 . 3210–3215 . October 1999 . 10540332 . 10.1002/(SICI)1521-4141(199910)29:10<3210::AID-IMMU3210>3.0.CO;2-W . free .
• Ghia P, Transidico P, Veiga JP, Schaniel C, Sallusto F, Matsushima K, Sallan SE, Rolink AG, Mantovani A, Nadler LM, Cardoso AA . 6 . Chemoattractants MDC and TARC are secreted by malignant B-cell precursors following CD40 ligation and support the migration of leukemia-specific T cells . Blood . 98 . 3 . 533–540 . August 2001 . 11468146 . 10.1182/blood.V98.3.533 . free .
• Morita A, Kikuoka S, Horikawa T, Bito T, Yamada H, Kanda M, Sasakura K, Tamaki M, Hirai K, Suzuki R, Sugita K . 6 . Evaluation of human thymus and activation-regulated chemokine concentrations in blood using a new sandwich ELISA based on monoclonal antibodies . Clinica Chimica Acta; International Journal of Clinical Chemistry . 322 . 1–2 . 67–75 . August 2002 . 12104083 . 10.1016/S0009-8981(02)00131-6 .
• Basu S, Schaefer TM, Ghosh M, Fuller CL, Reinhart TA . Molecular cloning and sequencing of 25 different rhesus macaque chemokine cDNAs reveals evolutionary conservation among C, CC, CXC, AND CX3C families of chemokines . Cytokine . 18 . 3 . 140–148 . May 2002 . 12126650 . 10.1006/cyto.2002.0875 .
• D'Ambrosio D, Albanesi C, Lang R, Girolomoni G, Sinigaglia F, Laudanna C . Quantitative differences in chemokine receptor engagement generate diversity in integrin-dependent lymphocyte adhesion . Journal of Immunology . 169 . 5 . 2303–2312 . September 2002 . 12193695 . 10.4049/jimmunol.169.5.2303 . free .
• Matsumoto N, Mukae H, Nakamura-Uchiyama F, Ashitani JI, Abe K, Katoh S, Kohno S, Nawa Y, Matsukura S . 6 . Elevated levels of thymus and activation-regulated chemokine (TARC) in pleural effusion samples from patients infested with Paragonimus westermani . Clinical and Experimental Immunology . 130 . 2 . 314–318 . November 2002 . 12390321 . 1906524 . 10.1046/j.1365-2249.2002.01985.x .
• Zheng X, Nakamura K, Tojo M, Oyama N, Nishibu A, Satoh M, Kakinuma T, Wakugawa M, Tamaki K, Kaneko F . 6 . TGF-beta1-mediated regulation of thymus and activation-regulated chemokine (TARC/CCL17) synthesis and secretion by HaCaT cells co-stimulated with TNF-alpha and IFN-gamma . Journal of Dermatological Science . 30 . 2 . 154–160 . November 2002 . 12413771 . 10.1016/S0923-1811(02)00071-3 .
• Kakinuma T, Nakamura K, Wakugawa M, Yano S, Saeki H, Torii H, Komine M, Asahina A, Tamaki K . 6 . IL-4, but not IL-13, modulates TARC (thymus and activation-regulated chemokine)/CCL17 and IP-10 (interferon-induced protein of 10kDA)/CXCL10 release by TNF-alpha and IFN-gamma in HaCaT cell line . Cytokine . 20 . 1 . 1–6 . October 2002 . 12441140 . 10.1006/cyto.2002.1965 .
• Uchida T, Suto H, Ra C, Ogawa H, Kobata T, Okumura K . Preferential expression of T(h)2-type chemokine and its receptor in atopic dermatitis . International Immunology . 14 . 12 . 1431–1438 . December 2002 . 12456591 . 10.1093/intimm/dxf109 . free .
• Jones K, Vari F, Keane C, Crooks P, Nourse JP, Seymour LA, Gottlieb D, Ritchie D, Gill D, Gandhi MK . 6 . Serum CD163 and TARC as disease response biomarkers in classical Hodgkin lymphoma . Clinical Cancer Research . 19 . 3 . 731–742 . February 2013 . 23224400 . 10.1158/1078-0432.CCR-12-2693 . free .

Notes and References

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4. Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O . The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4 . The Journal of Biological Chemistry . 272 . 23 . 15036–15042 . June 1997 . 9169480 . 10.1074/jbc.272.23.15036 . free .
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32. Nomiyama H, Imai T, Kusuda J, Miura R, Callen DF, Yoshie O . Assignment of the human CC chemokine gene TARC (SCYA17) to chromosome 16q13 . Genomics . 40 . 1 . 211–213 . February 1997 . 9070951 . 10.1006/geno.1996.4552 .
33. Nomiyama H, Imai T, Kusuda J, Miura R, Callen DF, Yoshie O . Human chemokines fractalkine (SCYD1), MDC (SCYA22) and TARC (SCYA17) are clustered on chromosome 16q13 . Cytogenetics and Cell Genetics . 81 . 1 . 10–11 . 1998 . 9691168 . 10.1159/000015000 . 2024-07-29 . 46851784 .