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CCL17
CCL17 is a powerful chemokine produced in the thymus and by antigen-presenting cells like dendritic cells, macrophages, and monocytes. 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.
CCL17 (CC chemokine ligand 17) was initially named TARC (thymus- and activation-regulated chemokine) when first isolated in 1996. It was later renamed CCL17 as the naming conventions for all cytokines were updated to standardize names.
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. 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. 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. Dendritic cells will produce large quantities of CCL17 when stimulated with IL-4 or TSLP.
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.
CCL17 was found to be highly expressed by the tumor cells of classic Hodgkin lymphoma. It can be detected by immunohistochemistry in >90% of cases in a diagnostic setting and is highly specific within B cell derived cancers. 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. 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. Its levels are increasing already several years prior to symptoms and diagnosis in many Hodgkin lymphoma patients.
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.
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.
CCL17 is known to help leukocytes (and especially eosinophils) target their response to skin-located pathogens. 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. 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. 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.
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CCL17
CCL17 is a powerful chemokine produced in the thymus and by antigen-presenting cells like dendritic cells, macrophages, and monocytes. 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.
CCL17 (CC chemokine ligand 17) was initially named TARC (thymus- and activation-regulated chemokine) when first isolated in 1996. It was later renamed CCL17 as the naming conventions for all cytokines were updated to standardize names.
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. 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. 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. Dendritic cells will produce large quantities of CCL17 when stimulated with IL-4 or TSLP.
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.
CCL17 was found to be highly expressed by the tumor cells of classic Hodgkin lymphoma. It can be detected by immunohistochemistry in >90% of cases in a diagnostic setting and is highly specific within B cell derived cancers. 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. 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. Its levels are increasing already several years prior to symptoms and diagnosis in many Hodgkin lymphoma patients.
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.
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.
CCL17 is known to help leukocytes (and especially eosinophils) target their response to skin-located pathogens. 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. 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. 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.