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Zou S, Liu B, Feng Y. CCL17, CCL22 and their receptor CCR4 in hematologic malignancies. Discov Oncol 2024; 15:412. [PMID: 39240278 PMCID: PMC11379839 DOI: 10.1007/s12672-024-01210-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 07/30/2024] [Indexed: 09/07/2024] Open
Abstract
Hematological malignancies (HM) are common malignant tumors with high morbidity and mortality rates, and are malignant diseases that seriously affect human health, with chemotherapy prone to recurrence and toxic side effects. Therefore, the development of precise, effective, and safe targeted therapeutic agents has become a hotspot in the current research of antitumor technology. More and more studies have shown that the interaction of C-C chemokine ligand 17 (CCL17) and C-C chemokine ligand 22 (CCL22) with the receptor C-C chemokine receptor type 4 (CCR4) promotes the immune escape of tumors and is closely related to the occurrence, development, and prognosis of hematological tumors. In this regard, we present a review on the expression and role of the CCL17/CCL22-CCR4 axis in HM, including lymphoma, leukemia, and multiple myeloma, with the aim of providing latest ideas and directions for the diagnosis and treatment of HM. In addition, we discuss the role and related mechanisms of HM therapeutic agents targeting the CCL17/CCL22-CCR4 axis and the potential of humanized anti-CCR4 antibodies for the treatment of HM.
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Affiliation(s)
- Shasha Zou
- Department of Hematology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Bo Liu
- Department of Key, Lab for Basic Pharmacology and Joint International Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.
| | - Yonghuai Feng
- Department of Hematology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
- Department of Hematology, Dongguan People's Hospital, Dongguan, China.
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2
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Wang QR, Liu SS, Min JL, Yin M, Zhang Y, Zhang Y, Tang XN, Li X, Liu SS. CCL17 drives fibroblast activation in the progression of pulmonary fibrosis by enhancing the TGF-β/Smad signaling. Biochem Pharmacol 2023; 210:115475. [PMID: 36870575 DOI: 10.1016/j.bcp.2023.115475] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 02/10/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023]
Abstract
Pulmonary fibrosis (PF) is a type of fatal respiratory diseases with limited therapeutic options and poor prognosis. The chemokine CCL17 plays crucial roles in the pathogenesis of immune diseases. Bronchoalveolar lavage fluid (BALF) CCL17 levels are significantly higher in patients with idiopathic PF (IPF) than in healthy volunteers. However, the source and function of CCL17 in PF remain unclear. Here, we demonstrated that the levels of CCL17 were increased in the lungs of IPF patients and mice with bleomycin (BLM)-induced PF. In particular, CCL17 were upregulated in alveolar macrophages (AMs) and antibody blockade of CCL17 protected mice against BLM-induced fibrosis and significantly reduced fibroblast activation. Mechanistic studies revealed that CCL17 interacted with its receptor CCR4 on fibroblasts, thereby activating the TGF-β/Smad signaling pathway to promote fibroblast activation and tissue fibrosis. Moreover, the knockdown of CCR4 by CCR4-siRNA or blockade by CCR4 antagonist C-021 was able to ameliorate PF pathology in mice. In summary, the CCL17-CCR4 axis is involved in the progression of PF, and targeting of CCL17 or CCR4 inhibits fibroblast activation and tissue fibrosis and may benefit patients with fibroproliferative lung diseases.
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Affiliation(s)
- Qian-Rong Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Suo-Si Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jia-Li Min
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Min Yin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yan Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yu Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xiang-Ning Tang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Shan-Shan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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3
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Nicolay JP, Albrecht JD, Alberti-Violetti S, Berti E. CCR4 in cutaneous T-cell lymphoma: Therapeutic targeting of a pathogenic driver. Eur J Immunol 2021; 51:1660-1671. [PMID: 33811642 DOI: 10.1002/eji.202049043] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/08/2021] [Accepted: 04/03/2021] [Indexed: 12/21/2022]
Abstract
New treatments are needed for patients with cutaneous T-cell lymphoma (CTCL), particularly for advanced mycosis fungoides (MF) and Sezary syndrome (SS). The immunopathology of MF and SS is complex, but recent advances in tumor microenvironment understanding have identified CCR4 as a promising therapeutic target. CCR4 is widely expressed on malignant T cells and Tregs in the skin and peripheral blood of patients with MF and SS. The interaction of CCR4 with its dominant ligands CCL17 and CCL22 plays a critical role in the development and progression of CTCL, facilitating the movement into, and accumulation of, CCR4-expressing T cells in the skin, and recruiting CCR4-expressing Tregs into the tumor microenvironment. Expression of CCR4 is upregulated at all stages of MF and in SS, increasing with advancing disease. Several CCR4-targeted therapies are being evaluated, including "chemotoxins" targeting CCR4 via CCL17, CCR4-directed chimeric antigen receptor-modified T-cell therapies, small-molecule CCR4 antagonists, and anti-CCR4 monoclonal antibodies. Only one is currently approved: mogamulizumab, a defucosylated, fully humanized, anti-CCR4, monoclonal antibody for the treatment of relapsed/refractory MF and SS. Clinical trial da1ta confirm that mogamulizumab is an effective and well-tolerated treatment for relapsed/refractory MF or SS, demonstrating the clinical value of targeting CCR4.
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Affiliation(s)
- Jan P Nicolay
- Department of Dermatology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.,Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section of Clinical and Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jana D Albrecht
- Department of Dermatology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.,Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section of Clinical and Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Silvia Alberti-Violetti
- Dipartimento di Medicina Interna, UOC Dermatologia, IRCCS Ca' Granda Foundation-Ospedale Maggiore Policlinico, Milan, Italy
| | - Emilio Berti
- Dipartimento di Medicina Interna, UOC Dermatologia, IRCCS Ca' Granda Foundation-Ospedale Maggiore Policlinico, Milan, Italy
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4
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Lan HR, Du WL, Liu Y, Mao CS, Jin KT, Yang X. Role of immune regulatory cells in breast cancer: Foe or friend? Int Immunopharmacol 2021; 96:107627. [PMID: 33862552 DOI: 10.1016/j.intimp.2021.107627] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022]
Abstract
Breast cancer (BC) is the most common cancer among women between the ages of 20 and 50, affecting more than 2.1 million people and causing the annual death of more than 627,000 women worldwide. Based on the available knowledge, the immune system and its components are involved in the pathogenesis of several malignancies, including BC. Cancer immunobiology suggests that immune cells can play a dual role and induce anti-tumor or immunosuppressive responses, depending on the tumor microenvironment (TME) signals. The most important effector immune cells with anti-tumor properties are natural killer (NK) cells, B, and T lymphocytes. On the other hand, immune and non-immune cells with regulatory/inhibitory phenotype, including regulatory T cells (Tregs), regulatory B cells (Bregs), tolerogenic dendritic cells (tDCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs), and regulatory natural killer cells (NKregs), can promote the growth and development of tumor cells by inhibiting anti-tumor responses, inducing angiogenesis and metastasis, as well as the expression of inhibitory molecules and suppressor mediators of the immune system. However, due to the complexity of the interaction and the modification in the immune cells' phenotype and the networking of the immune responses, the exact mechanism of action of the immunosuppressive and regulatory cells is not yet fully understood. This review article reviews the immune responses involved in BC as well as the role of regulatory and inhibitory cells in the pathogenesis of the disease. Finally, therapeutic approaches based on inhibition of immunosuppressive responses derived from regulatory cells are discussed.
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Affiliation(s)
- Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, PR China
| | - Wen-Lin Du
- Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, PR China; Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, PR China
| | - Yuyao Liu
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, PR China
| | - Chun-Sen Mao
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, PR China
| | - Ke-Tao Jin
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, PR China
| | - Xue Yang
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, PR China.
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Ollila TA, Sahin I, Olszewski AJ. Mogamulizumab: a new tool for management of cutaneous T-cell lymphoma. Onco Targets Ther 2019; 12:1085-1094. [PMID: 30799938 PMCID: PMC6369856 DOI: 10.2147/ott.s165615] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) poses unique treatment challenges, given its range of presentations and numerous systemic therapy options. These options often lack comparative evidence or are characterized by low response rates and short remission duration in relapsed/refractory disease. The approval of mogamulizumab, a humanized, glycoengineered IgG1κ monoclonal antibody targeting the chemokine receptor type 4 (CCR4) chemokine receptor, brings a novel tool into the spectrum of treatment options for advanced CTCL and adult T-cell leukemia/lymphoma (ATLL). CCR4 is expressed in almost all cases of ATLL, and in a majority of CTCLs, particularly when blood involvement is present. In a Phase III randomized trial, mogamulizumab was associated with 28% overall response rate among patients with relapsed CTCL, median progression-free survival of 7.7 months, and median duration of remission of 14.1 months. Responses are more frequent among patients with Sézary syndrome and within the blood compartment. Common adverse effects include rash and infusion reactions, which are usually low grade. Sentinel reports indicate that exposure to mogamulizumab may result in severe or refractory graft vs host disease after allogeneic bone marrow transplantation, highlighting the need for vigilance and expert management. Further research may establish incremental efficacy of combining mogamulizumab with cytotoxic or immunomodulatory agents in CTCL, ATLL, and possibly other lymphomas and even solid tumors.
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Affiliation(s)
- Thomas A Ollila
- Department of Medicine, Alpert Medical School of Brown University, Providence, RI, USA, .,Department of Medicine, Division of Hematology-Oncology, Rhode Island Hospital, Providence, RI, USA,
| | - Ilyas Sahin
- Department of Medicine, Alpert Medical School of Brown University, Providence, RI, USA, .,Department of Medicine, Division of Hematology-Oncology, Rhode Island Hospital, Providence, RI, USA,
| | - Adam J Olszewski
- Department of Medicine, Alpert Medical School of Brown University, Providence, RI, USA, .,Department of Medicine, Division of Hematology-Oncology, Rhode Island Hospital, Providence, RI, USA,
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6
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Madhumathi J, Devilakshmi S, Sridevi S, Verma RS. Immunotoxin therapy for hematologic malignancies: where are we heading? Drug Discov Today 2016; 21:325-32. [DOI: 10.1016/j.drudis.2015.05.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 03/04/2015] [Accepted: 05/01/2015] [Indexed: 12/19/2022]
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Santulli-Marotto S, Wheeler J, Lacy ER, Boakye K, Luongo J, Wu SJ, Ryan M. CCL22-specific Antibodies Reveal That Engagement of Two Distinct Binding Domains on CCL22 Is Required for CCR4-mediated Function. Monoclon Antib Immunodiagn Immunother 2015; 34:373-80. [DOI: 10.1089/mab.2015.0039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
| | - John Wheeler
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Eilyn R. Lacy
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Ken Boakye
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Jennifer Luongo
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Sheng-Jiun Wu
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Mary Ryan
- Janssen Research & Development, LLC, Spring House, Pennsylvania
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8
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Hiyoshi M, Okuma K, Tateyama S, Takizawa K, Saito M, Kuramitsu M, Araki K, Morishita K, Okada S, Yamamoto N, Biragyn A, Yamaguchi K, Hamaguchi I. Furin-dependent CCL17-fused recombinant toxin controls HTLV-1 infection by targeting and eliminating infected CCR4-expressing cells in vitro and in vivo. Retrovirology 2015; 12:73. [PMID: 26289727 PMCID: PMC4545545 DOI: 10.1186/s12977-015-0199-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 08/12/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) infection. However, there are no therapies to prevent ATL development in high-risk asymptomatic carriers. To develop a therapy targeting HTLV-1-infected cells that are known to express CCR4 frequently, we tested whether truncated Pseudomonas exotoxin (PE38) fused to a CCR4 ligand, CCL17/thymus and activation-regulated chemokine (TARC), selectively eliminates such cells. RESULTS Our data show that TARC-PE38 efficiently killed HTLV-1-infected cell lines. It also shrank HTLV-1-associated solid tumors in an infected-cell-engrafted mouse model. In HTLV-1-positive humanized mice, TARC-PE38 markedly inhibited the proliferation of HTLV-1-infected human CD4(+)CD25(+) or CD4(+)CD25(+)CCR4(+) cells and reduced the proviral loads (PVLs) in peripheral blood mononuclear cells (PBMCs). Importantly, TARC-PE38 significantly reduced the PVLs in PBMCs obtained from asymptomatic carriers. We show that the cytotoxicity of TARC-PE38 is mediated by the expression of the proprotein convertase, furin. The expression of furin was enhanced in HTLV-1-infected cells and correlated positively with PVLs in HTLV-1-infected individuals, suggesting that infected cells are more susceptible to TARC-PE38 than normal cells. CONCLUSIONS TARC-PE38 robustly controls HTLV-1 infection by eliminating infected cells in both a CCR4- and furin-dependent manner, indicating the excellent therapeutic potential of TARC-PE38.
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Affiliation(s)
- Masateru Hiyoshi
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan.
| | - Kazu Okuma
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan.
| | - Seiji Tateyama
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan. .,Medical Facilities Support Department, Micron Inc., Chiyoda-ku, Tokyo, 100-0005, Japan.
| | - Kazuya Takizawa
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan.
| | - Masumichi Saito
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan.
| | - Madoka Kuramitsu
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan.
| | - Kumiko Araki
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan.
| | - Kazuhiro Morishita
- Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan.
| | - Seiji Okada
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan.
| | - Naoki Yamamoto
- Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
| | - Arya Biragyn
- Immunoregulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD, 21224, USA.
| | - Kazunari Yamaguchi
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan.
| | - Isao Hamaguchi
- Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Musashimurayama, Tokyo, 208-0011, Japan.
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Hu SCS. Mycosis fungoides and Sézary syndrome: Role of chemokines and chemokine receptors. World J Dermatol 2015; 4:69-79. [DOI: 10.5314/wjd.v4.i2.69] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/16/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
Mycosis fungoides is the most common form of cutaneous T-cell lymphoma (CTCL), and is characterized by a clonal expansion of malignant CD4+ T lymphocytes with skin-homing properties. Clinically and pathologically, mycosis fungoides can be categorized into patch, plaque and tumor stages. The clinical course of mycosis fungoides is usually chronic and indolent, but a proportion of patients may develop progressive disease with peripheral blood, lymph node and visceral organ involvement. Sézary syndrome is an aggressive leukemic form of CTCL characterized by a clonal population of malignant T cells in the peripheral blood. Various forms of skin-directed and systemic treatments are available for mycosis fungoides and Sézary syndrome. However, current treatments are generally not curative, and can only control the disease. Currently, the etiology and pathogenesis of mycosis fungoides and Sézary syndrome are not well defined. Proposed mechanisms include chronic antigenic stimulation by infectious agents, expression of specific adhesion molecules, altered cytokine production, mutations of oncogenes and tumor suppressor genes, and avoidance of apoptosis. In recent years, a number of chemokine receptors and their corresponding chemokine ligands have been found to contribute to the migration and survival of lymphoma cells in mycosis fungoides and Sézary syndrome, including CC chemokine receptor 4 (CCR4), CCR10, C-X-C chemokine receptor type 4 (CXCR4), CCR7, CCR3 and CXCR3. Since chemokines and chemokine receptors have been found to play important roles in the pathophysiology of mycosis fungoides and Sézary syndrome, they may be potentially useful targets for the development of new treatments for these diseases in the future.
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Santulli-Marotto S, Fisher J, Petley T, Boakye K, Panavas T, Luongo J, Kavalkovich K, Rycyzyn M, Wu B, Gutshall L, Coelho A, Hogaboam CM, Ryan M. Surrogate antibodies that specifically bind and neutralize CCL17 but not CCL22. Monoclon Antib Immunodiagn Immunother 2014; 32:162-71. [PMID: 23750473 DOI: 10.1089/mab.2012.0112] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The chemokines CCL17 (TARC) and CCL22 (MDC) function through the same receptor, CCR4, but have been proposed to differentially affect the immune response. To better understand the role of the individual ligands, a panel of rat anti-mouse CCL17 surrogate antibodies was generated that can be used to differentiate CCL17 and CCL22 function in vitro and in vivo. We have successfully identified a panel of neutralizing antibodies by screening hybridomas for the ability to inhibit CCL17-mediated calcium mobilization. Chemotaxis in response to CCL17 is also inhibited, providing further evidence that the antibodies in this panel are antagonistic. Using a recombinant cell line expressing human CCR4, we show that the antibodies block β-arrestin recruitment as evidence that the antibodies are specifically blocking CCL17 signaling through CCR4. The antibodies within this panel inhibit calcium mobilization with varying potency in the calcium flux assay, having apparent IC50 ranging from approximately 1 to >400 ng/mL. Although both CCL17 and CCL22 function through CCR4, only a single antibody was identified as having detectable binding to CCL22. This panel of CCL17-specific antibodies provides tools that can be used to differentiate CCL17 and CCL22 function through CCR4 interaction in vitro and in vivo.
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Abstract
The involvement of Bregs in cancer remains poorly understood despite their well-documented regulation of responses to the self and protection from harmful autoimmunity. We recently discovered a unique regulatory B cell subset evoked by breast cancer to mediate protection of metastasizing cancer cells. These results together with the wealth of findings of the last 40 years on B cells in tumorigenesis suggest the existence of additional cancer Bregs modulating anticancer responses. To facilitate the search for them, here we provide our detailed protocol for the characterization and generation of tumor-evoked regulatory B cells. Wherever applicable, we also discuss nuances and uniqueness of a Breg study in cancer to warn potential pitfalls.
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Santulli-Marotto S, Boakye K, Lacy E, Wu SJ, Luongo J, Kavalkovich K, Coelho A, Hogaboam CM, Ryan M. Engagement of two distinct binding domains on CCL17 is required for signaling through CCR4 and establishment of localized inflammatory conditions in the lung. PLoS One 2013; 8:e81465. [PMID: 24339934 PMCID: PMC3855316 DOI: 10.1371/journal.pone.0081465] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Accepted: 10/14/2013] [Indexed: 12/20/2022] Open
Abstract
CCL17 (TARC) function can be completely abolished by mAbs that block either one of two distinct sites required for CCR4 signaling. This chemokine is elevated in sera of asthma patients and is responsible for establishing inflammatory sites through CCR4-mediated recruitment of immune cells. CCL17 shares the GPCR CCR4, with CCL22 (MDC) but these two chemokines differentially affect the immune response. To better understand chemokine mediated effects through CCR4, we have generated chimeric anti-mouse CCL17 surrogate antibodies that inhibit function of this ligand in vitro and in vivo. The affinities of the surrogate antibodies for CCL17 range from 685 pM for B225 to 4.9 nM for B202. One antibody, B202, also exhibits weak binding to CCL22 (KD∼2 µM) and no binding to CCL22 is detectable with the second antibody, B225. In vitro, both antibodies inhibit CCL17-mediated calcium mobilization, β-arrestin recruitment and chemotaxis; B202 can also partially inhibit CCL22-mediated β-arrestin recruitment. Both B202 and B225 antibodies neutralize CCL17 in vivo as demonstrated by reduction of methacholine-induced airway hyperreactivity in the A. fumigatus model of asthma. That both antibodies block CCL17 function but only B202 shows any inhibition of CCL22 function suggests that they bind CCL17 at different sites. Competition binding studies confirm that these two antibodies recognize unique epitopes that are non-overlapping despite the small size of CCL17. Taking into consideration the data from both the functional and binding studies, we propose that effective engagement of CCR4 by CCL17 involves two distinct binding domains and interaction with both is required for signaling.
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Affiliation(s)
- Sandra Santulli-Marotto
- Janssen Research & Development, Spring House, Pennsylvania, United States of America
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Ken Boakye
- Janssen Research & Development, Spring House, Pennsylvania, United States of America
| | - Eilyn Lacy
- Janssen Research & Development, Spring House, Pennsylvania, United States of America
| | - Sheng-Jiun Wu
- Janssen Research & Development, Spring House, Pennsylvania, United States of America
| | - Jennifer Luongo
- Janssen Research & Development, Spring House, Pennsylvania, United States of America
| | - Karl Kavalkovich
- Janssen Research & Development, Spring House, Pennsylvania, United States of America
| | - Ana Coelho
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Cory M. Hogaboam
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Mary Ryan
- Janssen Research & Development, Spring House, Pennsylvania, United States of America
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13
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Honjo A, Ogawa H, Azuma M, Tezuka T, Sone S, Biragyn A, Nishioka Y. Targeted reduction of CCR4⁺ cells is sufficient to suppress allergic airway inflammation. Respir Investig 2013; 51:241-9. [PMID: 24238232 PMCID: PMC5846619 DOI: 10.1016/j.resinv.2013.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 04/04/2013] [Accepted: 04/30/2013] [Indexed: 06/02/2023]
Abstract
BACKGROUND Bronchial asthma is characterized by allergic airway inflammation involving C-C chemokine receptor type 4 (CCR4)-positive Th2 cells. As such, we hypothesize that the disease can be alleviated by targeted-elimination of CCR4⁺ cells. Thymus and activation-regulated chemokine (TARC)-PE38, a TARC fused the exotoxin fragment PE38 from Pseudomonas aeruginosa, has been shown to efficiently kill CCR4⁺ cells by delivering the exotoxin fragment PE38 into CCR4⁺ cells. To test our hypothesis, we examined whether TARC-PE38 could suppress allergic airway inflammation in a mouse model of house dust mite (HDM)-induced allergic airway inflammation. METHODS We evaluated the effect of TARC-PE38 on the major characteristics of HDM-induced allergic airway inflammation. Airway hyperresponsiveness, lung histopathology, lung Th1/Th2 cell populations, and concentrations of Th1/Th2 cytokines in the lungs were assessed in HDM-sensitized and challenged mice in the presence and absence of TARC-PE38. RESULTS TARC-PE38 efficiently suppressed allergic airway inflammation by significantly reducing airway hyperresponsiveness, the overall area of inflammation, and goblet cell hyperplasia. In HDM-sensitized and challenged mice, TARC-PE38 specifically reduced the numbers of CCR4⁺ cells. This reduction was associated with a significant decrease in the production of Th2 cytokines in the airway,and a decrease in the number of leukocytes, including macrophages, eosinophils and lymphocytes, within the subepithelial area of the lungs and airway lumen. TARC-PE38 had noeffect on Th1 cells. CONCLUSION Our data suggest that the elimination of CCR4⁺ cells via TARC-PE38 treatment is sufficient to control allergic airway inflammation and airway hyperresponsiveness.
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Affiliation(s)
- Akifumi Honjo
- Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
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14
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Inhibition of lung metastasis by chemokine CCL17-mediated in vivo silencing of genes in CCR4+ Tregs. J Immunother 2013; 36:258-67. [PMID: 23603860 DOI: 10.1097/cji.0b013e318294357c] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Despite significant attractiveness of antisense oligonucleotide/RNAi technology, its clinical application has been precluded by a lack of methods for targeted delivery and transduction of primary immune cells in vivo. Here, we devised a chemokine CCL17-based strategy (TARC-arp) that transiently silences expression of genes in immune cells by delivering inhibitory oligonucleotides through their chemokine receptors. In modeling studies using mice with established 4T1.2 breast cancer, we show that IL10 produced by CCR4 cells, in particular FoxP3 regulatory T cells (Tregs), plays an important role in lung metastasis. As such, TARC-arp-mediated silencing of IL10 or FoxP3 in CCR4 Tregs is sufficient to block lung metastasis. Thus, we provide a simple solution that circumvents the problems of RNAi use in vivo, indicating that a disease outcome can be successfully controlled by delivering inhibitory oligonucleotides with chemokines to inactivate a selective subset of immune cells.
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15
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Bodogai M, Lee Chang C, Wejksza K, Lai J, Merino M, Wersto RP, Gress RE, Chan AC, Hesdorffer C, Biragyn A. Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L. Cancer Res 2013; 73:2127-38. [PMID: 23365136 DOI: 10.1158/0008-5472.can-12-4184] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The possible therapeutic benefits of B-cell depletion in combating tumoral immune escape have been debated. In support of this concept, metastasis of highly aggressive 4T1 breast cancer cells in mice can be abrogated by inactivation of tumor-evoked regulatory B cells (tBreg). Here, we report the unexpected finding that B-cell depletion by CD20 antibody will greatly enhance cancer progression and metastasis. Both murine and human tBregs express low levels of CD20 and, as such, anti-CD20 mostly enriches for these cells. In the 4T1 model of murine breast cancer, this effect of enriching for tBregs suggests that B-cell depletion by anti-CD20 may not be beneficial at all in some cancers. In contrast, we show that in vivo-targeted stimulation of B cells with CXCL13-coupled CpG oligonucleotides (CpG-ODN) can block cancer metastasis by inhibiting CD20(Low) tBregs. Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B-expressing cytolytic CD8(+) T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo.
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Affiliation(s)
- Monica Bodogai
- Immunotherapeutic Section, National Institute on Aging, Baltimore, MD 21224, USA
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16
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Induction of antitumor immunity ex vivo using dendritic cells transduced with fowl pox vector expressing MUC1, CEA, and a triad of costimulatory molecules (rF-PANVAC). J Immunother 2013; 35:555-69. [PMID: 22892452 DOI: 10.1097/cji.0b013e31826a73de] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The fowl pox vector expressing the tumor-associated antigens, mucin-1 and carcinoembryonic antigen in the context of costimulatory molecules (rF-PANVAC) has shown promise as a tumor vaccine. However, vaccine-mediated expansion of suppressor T-cell populations may blunt clinical efficacy. We characterized the cellular immune response induced by ex vivo dendritic cells (DCs) transduced with (rF)-PANVAC. Consistent with the functional characteristics of potent antigen-presenting cells, rF-PANVAC-DCs demonstrated strong expression of mucin-1 and carcinoembryonic antigen and costimulatory molecules, CD80, CD86, and CD83; decreased levels of phosphorylated STAT3, and increased levels of Tyk2, Janus kinase 2, and STAT1. rF-PANVAC-DCs stimulated expansion of tumor antigen-specific T cells with potent cytolytic capacity. However, rF-PANVAC-transduced DCs also induced the concurrent expansion of FOXP3 expressing CD4CD25 regulatory T cells (Tregs) that inhibited T-cell activation. Moreover, Tregs expressed high levels of Th2 cytokines [interleukin (IL)-10, IL-4, IL-5, and IL-13] together with phosphorylated STAT3 and STAT6. In contrast, the vaccine-expanded Treg population expressed high levels of Th1 cytokines IL-2 and interferon-γ and the proinflammatory receptor-related orphan receptor γt (RORγt) and IL-17A suggesting that these cells may share effector functions with conventional TH17 T cells. These data suggest that Tregs expanded by rF-PANVAC-DCs, exhibit immunosuppressive properties potentially mediated by Th2 cytokines, but simultaneous expression of Th1 and Th17-associated factors suggests a high degree of plasticity.
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17
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Lee CH, Hwang STY. Pathophysiology of chemokines and chemokine receptors in dermatological science: A focus on psoriasis and cutaneous T-cell lymphoma. DERMATOL SIN 2012. [DOI: 10.1016/j.dsi.2012.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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18
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Madhumathi J, Verma RS. Therapeutic targets and recent advances in protein immunotoxins. Curr Opin Microbiol 2012; 15:300-9. [PMID: 22647353 DOI: 10.1016/j.mib.2012.05.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Accepted: 05/14/2012] [Indexed: 12/25/2022]
Abstract
Targeted therapy has replaced the conventional methods of disease management with the advances in recombinant technology and increased understanding of molecular mechanisms of diseases. The immunotoxin strategy for diseases like cancer and a variety of autoimmune disorders has been used successfully in the past since its discovery. Since bacterial, fungal and plant toxins have various limitations like toxicity and immunogenicity, studies on fully humanized immunotoxins have gained attraction recently, which reduced toxicity significantly. Improved methods of antibody engineering have led to the emergence of various new formats of immunotoxins. This review summarizes the target moieties used in immunotoxin constructs in different diseases and describes the recent advances in immunotoxin targeting.
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Affiliation(s)
- Madhumathi J
- Stem Cell and Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, Tamilnadu, India
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19
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Biragyn A, Longo DL. Neoplastic "Black Ops": cancer's subversive tactics in overcoming host defenses. Semin Cancer Biol 2012; 22:50-9. [PMID: 22257681 DOI: 10.1016/j.semcancer.2012.01.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 01/04/2012] [Indexed: 01/07/2023]
Abstract
Metastatic cancer is usually an incurable disease. Cancers have a broad repertoire of subversive tactics to defeat the immune system. They mimic self, they down-regulate MHC molecules so that T cells are blind to their presence, they interfere with antigen presentation, and they produce factors that can kill T cells or paralyze their response to antigens. Furthermore, the same powerful machinery designed to prevent harmful autoimmune responses is also acting to protect cancers. In particular, cancer is protected with the help of so-called regulatory immune cells. These unique subsets of cells, represented by almost every immune cell type, function to control responses of effector immune cells. In this review, we will discuss the evidence that cancer actively promotes cross-talk of regulatory immune cells to evade immunosurveillance. We will also discuss the role of a newly described cell type, regulatory B cells, by emphasizing their importance in suppression of antitumor immune responses. Thus, cancer not only directly suppresses immune function, but also recruits components of the immune system to become traitors and protect the tumor from immune attack.
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Affiliation(s)
- Arya Biragyn
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD 21224, United States.
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20
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Hu Y, Zhang L, Wu R, Han R, Jia Y, Jiang Z, Cheng M, Gan J, Tao X, Zhang Q. Specific killing of CCR9 high-expressing acute T lymphocytic leukemia cells by CCL25 fused with PE38 toxin. Leuk Res 2011; 35:1254-60. [PMID: 21295855 DOI: 10.1016/j.leukres.2011.01.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Revised: 01/14/2011] [Accepted: 01/15/2011] [Indexed: 12/18/2022]
Abstract
We have previously demonstrated that CCR9 plays a pivotal role in drug resistance and invasion in human acute T-lymphocytic leukemia (T-ALL). In this study, we investigated whether the MOLT4 cells, which naturally express CCR9 at high levels, can be successfully killed by the specific ligand, CCL25 fused to Pseudomonas exotoxin 38 (PE38) toxin. Our results demonstrated that CCL25-PE38 was able to specifically kill MOLT4 cells via apoptosis induction, and suppress the growth of CCR9(+) tumors. This work shows that CCR9 high-expressing human T-ALL cells can be successfully killed by delivering PE38 toxin fused to the ligand CCL25.
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Affiliation(s)
- Yi Hu
- Department of Immunology, School of Basic Medical Science, Wuhan University, Wuchang, Wuhan, China
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21
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Khan AR, Dovedi SJ, Wilkinson RW, Pritchard DI. Tumor infiltrating regulatory T cells: tractable targets for immunotherapy. Int Rev Immunol 2011; 29:461-84. [PMID: 20839911 DOI: 10.3109/08830185.2010.508854] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Several studies have linked tumor-infiltration by regulatory T cells with poor patient outcome. Targeting the mechanisms by which regulatory T cells traffic to and persist in the tumor may circumvent tumor immune-escape by de-restricting T cell-mediated cytotoxicity. In this review, we describe the principle axes that govern regulatory T cell migration and the mechanisms that underpin their immunosuppressive activity in cancer. Inhibiting either the migration or function of regulatory T cells may enhance host-anti-cancer immune responses and as such are attractive and tractable targets for therapeutic intervention.
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Affiliation(s)
- Adnan R Khan
- Doctoral Training Centre for Targeted Therapeutics, School of Pharmacy, University of Nottingham, Nottingham, UK
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22
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Abstract
IMPORTANCE OF THE FIELD Psoriasis is a common, chronic autoimmune disease of the skin. Despite a number of effective treatments, new therapies are needed with enhanced efficacy, safety and convenience. Chemokine receptors are GPCRs that control leukocyte trafficking, and like other GPCRs, are good potential drug targets. The chemokine receptor CCR6 is expressed on the T(H)17 subset of CD4(+) T cells, which produces IL-17A/F, IL-22, TNF-alpha and other cytokines, and which has been implicated in the pathogenesis of psoriasis. CCR6 and its ligand, CCL20/MIP-3alpha, are highly expressed in psoriatic skin and CCR6 is necessary for the pathology induced in a mouse model of psoriasis-like inflammation. AREAS COVERED IN THIS REVIEW This review summarizes the evidence for the importance of the IL-23/T(H)17 axis, and in particular CCR6 and CCL20 in psoriasis, dating from 2000 to the present, and discusses the possibility of inhibiting CCR6 as a treatment for the disease. WHAT THE READER WILL GAIN The review informs the reader of the current thinking on the mechanisms of inflammation in psoriasis and the possible roles for CCR6 (and CCL20) in disease pathogenesis. TAKE HOME MESSAGE We conclude that CCR6 should be investigated as a potential therapeutic target in psoriasis.
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Affiliation(s)
- Michael N. Hedrick
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Anke S. Lonsdorf
- Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Sam T. Hwang
- Department of Dermatology, Medical College of Wisconsin, Froedtert Clinic East, Milwaukee, Wisconsin, USA
| | - Joshua M. Farber
- Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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23
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Fridlender ZG, Buchlis G, Kapoor V, Cheng G, Sun J, Singhal S, Crisanti MC, Crisanti C, Wang LCS, Heitjan D, Snyder LA, Albelda SM. CCL2 blockade augments cancer immunotherapy. Cancer Res 2009; 70:109-18. [PMID: 20028856 DOI: 10.1158/0008-5472.can-09-2326] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Altering the immunosuppressive microenvironment that exists within a tumor will likely be necessary for cancer vaccines to trigger an effective antitumor response. Monocyte chemoattractant proteins (such as CCL2) are produced by many tumors and have both direct and indirect immunoinhibitory effects. We hypothesized that CCL2 blockade would reduce immunosuppression and augment vaccine immunotherapy. Anti-murine CCL2/CCL12 monoclonal antibodies were administered in three immunotherapy models: one aimed at the human papillomavirus E7 antigen expressed by a non-small cell lung cancer (NSCLC) line, one targeted to mesothelin expressed by a mesothelioma cell line, and one using an adenovirus-expressing IFN-alpha to treat a nonimmunogenic NSCLC line. We evaluated the effect of the combination treatment on tumor growth and assessed the mechanism of these changes by evaluating cytotoxic T cells, immunosuppressive cells, and the tumor microenvironment. Administration of anti-CCL2/CCL12 antibodies along with the vaccines markedly augmented efficacy with enhanced reduction in tumor volume and cures of approximately half of the tumors. The combined treatment generated more total intratumoral CD8+ T cells that were more activated and more antitumor antigen-specific, as measured by tetramer evaluation. Another important potential mechanism was reduction in intratumoral T regulatory cells. CCL2 seems to be a key proximal cytokine mediating immunosuppression in tumors. Its blockade augments CD8+ T-cell immune response to tumors elicited by vaccines via multifactorial mechanisms. These observations suggest that combining CCL2 neutralization with vaccines should be considered in future immunotherapy trials.
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Affiliation(s)
- Zvi G Fridlender
- Thoracic Oncology Research Laboratory and Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
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Su H, Jack M, McIntosh LM, Perdomo L, Choy BS, Finck BK, McDonald JR. Clinical grade production and characterization of a fusion protein comprised of the chemokine CCL2-ligand genetically fused to a mutated and truncated form of the Shiga A1 subunit. Protein Expr Purif 2009; 66:149-57. [DOI: 10.1016/j.pep.2009.02.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Revised: 02/24/2009] [Accepted: 02/24/2009] [Indexed: 01/11/2023]
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Olkhanud PB, Baatar D, Bodogai M, Hakim F, Gress R, Anderson RL, Deng J, Xu M, Briest S, Biragyn A. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells. Cancer Res 2009; 69:5996-6004. [PMID: 19567680 DOI: 10.1158/0008-5472.can-08-4619] [Citation(s) in RCA: 227] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer metastasis is a leading cause of cancer morbidity and mortality. More needs to be learned about mechanisms that control this process. In particular, the role of chemokine receptors in metastasis remains controversial. Here, using a highly metastatic breast cancer (4T1) model, we show that lung metastasis is a feature of only a proportion of the tumor cells that express CCR4. Moreover, the primary tumor growing in mammary pads activates remotely the expression of TARC/CCL17 and MDC/CCL22 in the lungs. These chemokines acting through CCR4 attract both tumor and immune cells. However, CCR4-mediated chemotaxis was not sufficient to produce metastasis, as tumor cells in the lung were efficiently eliminated by natural killer (NK) cells. Lung metastasis required CCR4(+) regulatory T cells (Treg), which directly killed NK cells using beta-galactoside-binding protein. Thus, strategies that abrogate any part of this process should improve the outcome through activation of effector cells and prevention of tumor cell migration. We confirm this prediction by killing CCR4(+) cells through delivery of TARC-fused toxins or depleting Tregs and preventing lung metastasis.
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Affiliation(s)
- Purevdorj B Olkhanud
- Laboratory of Immunology, National Institute on Aging, Baltimore, Maryland 21224, USA
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26
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Lonsdorf AS, Hwang ST, Enk AH. Chemokine receptors in T-cell-mediated diseases of the skin. J Invest Dermatol 2009; 129:2552-66. [PMID: 19474804 DOI: 10.1038/jid.2009.122] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The chemokine/chemokine receptor network is an integral element of the complex system of homeostasis and immunosurveillance. Initially studied because of their role in coordinating tissue-specific migration and activation of leucocytes, chemokines have been implicated in the pathogenesis of various malignancies and diseases with strong inflammatory components. We discuss recent findings suggesting a critical involvement of chemokine receptor interactions in the immunopathogenesis of classical inflammatory skin disorders such as psoriasis and atopic dermatitis, as well as neoplastic diseases with a T-cell origin, such as mycosis fungoides. A deeper understanding of the underlying contribution of the chemokine network in the disease processes is key for the development of selective targeted immunotherapeutics that may meet the delicate balance between efficacy and safety.
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Affiliation(s)
- Anke S Lonsdorf
- Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany.
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27
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Abstract
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.
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Abstract
CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are critically involved in different immune processes. In models of lipopolysaccharide-induced shock, CCR4-deficient (CCR4(-/-)) mice showed improved survival rates associated with attenuated proinflammatory cytokine release. Using CCR4(-/-) mice with a C57BL/6 background, this study describes for the first time the role of CCR4 in a murine model of polymicrobial abdominal sepsis, the colon ascendens stent peritonitis (CASP). CASP-induced sepsis led to a massive downregulation of CCR4 in lymphoid and nonlymphoid tissues, whereas the expression of CCL17 and CCL22 was independent of the presence of CCR4. After CASP, CCR4(-/-) animals showed a strongly enhanced bacterial clearance in several organs but not in the peritoneal lavage fluid and the blood. In addition, significantly reduced levels of proinflammatory cytokines/chemokines were measured in organ supernatants as well as in the sera of CCR4(-/-) mice. CCR4 deficiency consequently resulted in an attenuated severity of systemic sepsis and a strongly improved survival rate after CASP or CASP with intervention. Thus, our data provide clear evidence that CCR4 plays a strictly detrimental role in the course of polymicrobial sepsis.
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Golay J, Introna M. Chemokines and antagonists in non-Hodgkin's lymphoma. Expert Opin Ther Targets 2008; 12:621-35. [DOI: 10.1517/14728222.12.5.621] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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