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1
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Wen P, Zhuo X, Wang L. Skin barrier dysfunction in cutaneous T-cell lymphoma: From pathogenic mechanism of barrier damage to treatment. Crit Rev Oncol Hematol 2025; 205:104559. [PMID: 39549893 DOI: 10.1016/j.critrevonc.2024.104559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 10/30/2024] [Accepted: 11/08/2024] [Indexed: 11/18/2024] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a group of non-Hodgkin lymphomas characterized by multiple erythematous patches, plaques, or even nodules on the skin. As the disease progresses, patients develop widespread pruritic skin lesions, leading to skin barrier dysfunction, which significantly impacts their quality of life, appearance, and social adaptation. The pathogenesis of CTCL is not fully understood. Recent studies have recognized the important role of skin barrier dysfunction in the development and progression of CTCL, yet a comprehensive review on this topic is lacking. This review summarizes recent findings on skin barrier dysfunction in CTCL, focusing on physical barrier dysfunction, chronic inflammation, and immune dysregulation. We also discuss current and potential therapies aimed at restoring barrier function in CTCL. By emphasizing the integration of barrier-centric approaches into CTCL management, this review provides valuable insights for improving treatment outcomes.
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Affiliation(s)
- Pengfei Wen
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
| | - Xiaoxue Zhuo
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
| | - Lin Wang
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
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2
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Kwantwi LB, Rosen ST, Querfeld C. The Tumor Microenvironment as a Therapeutic Target in Cutaneous T Cell Lymphoma. Cancers (Basel) 2024; 16:3368. [PMID: 39409988 PMCID: PMC11482616 DOI: 10.3390/cancers16193368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 09/27/2024] [Accepted: 09/28/2024] [Indexed: 10/19/2024] Open
Abstract
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite the substantial improvement in early-stage diagnosis and treatments, some patients still progress to the advanced stage with an elusive underpinning mechanism. While this unsubstantiated disease mechanism coupled with diverse clinical outcomes poses challenges in disease management, emerging evidence has implicated the tumor microenvironment in the disease process, thus revealing a promising therapeutic potential of targeting the tumor microenvironment. Notably, malignant T cells can shape their microenvironment to dampen antitumor immunity, leading to Th2-dominated responses that promote tumor progression. This is largely orchestrated by alterations in cytokines expression patterns, genetic dysregulations, inhibitory effects of immune checkpoint molecules, and immunosuppressive cells. Herein, the recent insights into the determining factors in the CTCL tumor microenvironment that support their progression have been highlighted. Also, recent advances in strategies to target the CTCL tumor micromovement with the rationale of improving treatment efficacy have been discussed.
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Affiliation(s)
- Louis Boafo Kwantwi
- Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA
- Beckman Research Institute, Duarte, CA 91010, USA
- Department of Anatomy and Neurobiology, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA
| | - Steven T Rosen
- Beckman Research Institute, Duarte, CA 91010, USA
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
| | - Christiane Querfeld
- Department of Pathology, City of Hope Medical Center, Duarte, CA 91010, USA
- Beckman Research Institute, Duarte, CA 91010, USA
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA 91010, USA
- Division of Dermatology, City of Hope Medical Center, Duarte, CA 91010, USA
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3
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Gordon ER, Fahmy LM, Trager MH, Adeuyan O, Lapolla BA, Schreidah CM, Geskin LJ. From Molecules to Microbes: Tracing Cutaneous T-Cell Lymphoma Pathogenesis through Malignant Inflammation. J Invest Dermatol 2024; 144:1954-1962. [PMID: 38703171 DOI: 10.1016/j.jid.2024.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/14/2024] [Accepted: 03/16/2024] [Indexed: 05/06/2024]
Abstract
The etiology of CTCL is a subject of extensive investigation. Researchers have explored links between CTCL and environmental chemical exposures, such as aromatic hydrocarbons (eg, pesticides and benzene), as well as infectious factors, including various viruses (eg, human T-lymphotropic virus [HTLV]-I and HTLV-II) and bacteria (eg, Staphylococcus aureus). There has been growing emphasis on the role of malignant inflammation in CTCL development. In this review, we synthesize studies of environmental and infectious exposures, along with research on the aryl hydrocarbon receptor and the involvement of pathogens in disease etiology, providing insight into the pathogenesis of CTCL.
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Affiliation(s)
- Emily R Gordon
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Lauren M Fahmy
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Megan H Trager
- Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA
| | - Oluwaseyi Adeuyan
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Brigit A Lapolla
- Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA
| | - Celine M Schreidah
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Larisa J Geskin
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA.
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Jung JM, Cho HS, Moon IJ, Won CH, Chang SE, Lee MW, Lee WJ. Prognostic implications of blood eosinophilia and tissue eosinophil infiltration in mycosis fungoides: a retrospective cohort study. Arch Dermatol Res 2024; 316:183. [PMID: 38762842 DOI: 10.1007/s00403-024-02909-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/07/2024] [Accepted: 04/26/2024] [Indexed: 05/20/2024]
Affiliation(s)
- Joon Min Jung
- Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Hye Soo Cho
- Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Ik Jun Moon
- Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Chong Hyun Won
- Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Sung Eun Chang
- Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Mi Woo Lee
- Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Woo Jin Lee
- Department of Dermatology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.
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Hu M, Scheffel J, Elieh-Ali-Komi D, Maurer M, Hawro T, Metz M. An update on mechanisms of pruritus and their potential treatment in primary cutaneous T-cell lymphoma. Clin Exp Med 2023; 23:4177-4197. [PMID: 37555911 PMCID: PMC10725374 DOI: 10.1007/s10238-023-01141-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/12/2023] [Indexed: 08/10/2023]
Abstract
Primary cutaneous T-cell lymphomas (CTCL), which include mycosis fungoides (MF) and Sézary syndrome (SS), are a group of lymphoproliferative disorders characterized by clonal accumulation of neoplastic T-lymphocytes in the skin. Severe pruritus, one of the most common and distressing symptoms in primary CTCL, can significantly impair emotional well-being, physical functioning, and interpersonal relationships, thus greatly reducing quality of life. Unfortunately, effectively managing pruritus remains challenging in CTCL patients as the underlying mechanisms are, as of yet, not fully understood. Previous studies investigating the mechanisms of itch in CTCL have identified several mediators and their corresponding antagonists used for treatment. However, a comprehensive overview of the mediators and receptors contributing to pruritus in primary CTCL is lacking in the current literature. Here, we summarize and review the mediators and receptors that may contribute to pruritus in primary CTCL to explore the mechanisms of CTCL pruritus and identify effective therapeutic targets using the PubMed and Web of Science databases. Studies were included if they described itch mediators and receptors in MF and SS. Overall, the available data suggest that proteases (mainly tryptase), and neuropeptides (particularly Substance P) may be of greatest interest. At the receptor level, cytokine receptors, MRGPRs, and TRP channels are most likely important. Future drug development efforts should concentrate on targeting these mediators and receptors for the treatment of CTCL pruritus.
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Affiliation(s)
- Man Hu
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Jörg Scheffel
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Daniel Elieh-Ali-Komi
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Marcus Maurer
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Tomasz Hawro
- Department of Dermatology, Allergology and Venereology, Institute and Comprehensive Center for Inflammation Medicine, University Medical Center Schleswig-Holstein, Lübeck, Germany.
| | - Martin Metz
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, Hindenburgdamm 27, 12203, Berlin, Germany.
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany.
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Han Z, Wu X, Qin H, Yuan YC, Schmolze D, Su C, Zain J, Moyal L, Hodak E, Sanchez JF, Lee PP, Feng M, Rosen ST, Querfeld C. Reprogramming of PD-1+ M2-like tumor-associated macrophages with anti-PD-L1 and lenalidomide in cutaneous T cell lymphoma. JCI Insight 2023; 8:e163518. [PMID: 37427589 PMCID: PMC10371344 DOI: 10.1172/jci.insight.163518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 05/19/2023] [Indexed: 07/11/2023] Open
Abstract
Cutaneous T cell lymphoma (CTCL) is a disfiguring and incurable disease characterized by skin-homing malignant T cells surrounded by immune cells that promote CTCL growth through an immunosuppressive tumor microenvironment (TME). Preliminary data from our phase I clinical trial of anti-programmed cell death ligand 1 (anti-PD-L1) combined with lenalidomide in patients with relapsed/refractory CTCL demonstrated promising clinical efficacy. In the current study, we analyzed the CTCL TME, which revealed a predominant PD-1+ M2-like tumor-associated macrophage (TAM) subtype with upregulated NF-κB and JAK/STAT signaling pathways and an aberrant cytokine and chemokine profile. Our in vitro studies investigated the effects of anti-PD-L1 and lenalidomide on PD-1+ M2-like TAMs. The combinatorial treatment synergistically induced functional transformation of PD-1+ M2-like TAMs toward a proinflammatory M1-like phenotype that gained phagocytic activity upon NF-κB and JAK/STAT inhibition, altered their migration through chemokine receptor alterations, and stimulated effector T cell proliferation. Lenalidomide was more effective than anti-PD-L1 in downregulation of the immunosuppressive IL-10, leading to decreased expression of both PD-1 and PD-L1. Overall, PD-1+ M2-like TAMs play an immunosuppressive role in CTCL. Anti-PD-L1 combined with lenalidomide provides a therapeutic strategy to enhance antitumor immunity by targeting PD-1+ M2-like TAMs in the CTCL TME.
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Affiliation(s)
- Zhen Han
- Division of Dermatology
- Beckman Research Institute
| | - Xiwei Wu
- Department of Computational and Quantitative Medicine
- Integrative Genomics Core
| | - Hanjun Qin
- Department of Computational and Quantitative Medicine
| | - Yate-Ching Yuan
- Department of Computational and Quantitative Medicine
- Center for informatics
| | | | - Chingyu Su
- Division of Dermatology
- Beckman Research Institute
| | - Jasmine Zain
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Lilach Moyal
- Department of Dermatology, Rabin Medical Center, Felsenstein Medical Research Center, Tel Aviv University, Tel Aviv, Israel
| | - Emmilia Hodak
- Department of Dermatology, Rabin Medical Center, Felsenstein Medical Research Center, Tel Aviv University, Tel Aviv, Israel
- Beilinson Hospital, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - James F Sanchez
- Beckman Research Institute
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Peter P Lee
- Beckman Research Institute
- Department of Immuno-Oncology, City of Hope, Duarte, California, USA
| | - Mingye Feng
- Beckman Research Institute
- Department of Immuno-Oncology, City of Hope, Duarte, California, USA
| | - Steven T Rosen
- Beckman Research Institute
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
| | - Christiane Querfeld
- Division of Dermatology
- Beckman Research Institute
- Department of Pathology, and
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California, USA
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7
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Molecular pathogenesis of Cutaneous T cell Lymphoma: Role of chemokines, cytokines, and dysregulated signaling pathways. Semin Cancer Biol 2022; 86:382-399. [PMID: 34906723 DOI: 10.1016/j.semcancer.2021.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/03/2021] [Accepted: 12/08/2021] [Indexed: 01/27/2023]
Abstract
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative neoplasms that exhibit a wide spectrum of immune-phenotypical, clinical, and histopathological features. The biology of CTCL is complex and remains elusive. In recent years, the application of next-generation sequencing (NGS) has evolved our understanding of the pathogenetic mechanisms, including genetic aberrations and epigenetic abnormalities that shape the mutational landscape of CTCL and represent one of the important pro-tumorigenic principles in CTCL initiation and progression. Still, identification of the major pathophysiological pathways including genetic and epigenetic components that mediate malignant clonal T cell expansion has not been achieved. This is of prime importance given the role of malignant T cell clones in fostering T helper 2 (Th2)-bias tumor microenvironment and fueling progressive immune dysregulation and tumor cell growth in CTCL patients, manifested by the secretion of Th2-associated cytokines and chemokines. Alterations in malignant cytokine and chemokine expression patterns orchestrate the inflammatory milieu and influence the migration dynamics of malignant clonal T cells. Here, we highlight recent insights about the molecular mechanisms of CTCL pathogenesis, emphasizing the role of cytokines, chemokines, and associated downstream signaling networks in driving immune defects, malignant transformation, and disease progression. In-depth characterization of the CTCL immunophenotype and tumoral microenvironment offers a facile opportunity to expand the therapeutic armamentarium of CTCL, an intractable malignant skin disease with poor prognosis and in dire need of curative treatment approaches.
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BenAyed-Guerfali D, Kifagi C, BenKridis-Rejeb W, Ammous-Boukhris N, Ayedi W, Khanfir A, Daoud J, Mokdad-Gargouri R. The Identification by Exome Sequencing of Candidate Genes in BRCA-Negative Tunisian Patients at a High Risk of Hereditary Breast/Ovarian Cancer. Genes (Basel) 2022; 13:genes13081296. [PMID: 35893033 PMCID: PMC9331434 DOI: 10.3390/genes13081296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/16/2022] [Accepted: 07/19/2022] [Indexed: 12/24/2022] Open
Abstract
(1) Background: Germline variants in BRCA1/BRCA2 genes explain about 20% of hereditary breast/ovarian cancer (HBOC) cases. In the present paper, we aim to identify genetic determinants in BRCA-negative families from the South of Tunisia. (2) Methods: Exome Sequencing (ES) was performed on the lymphocyte DNA of patients negative for BRCA mutations from each Tunisian family with a high risk of HBOC. (3) Results: We focus on the canonical genes associated with HBOC and identified missense variants in DNA damage response genes, such as ATM, RAD52, and RAD54; however, no variants in PALB2, Chek2, and TP53 genes were found. To identify novel candidate genes, we selected variants harboring a loss of function and identified 17 stop-gain and 11 frameshift variants in genes not commonly known to be predisposed to HBOC. Then, we focus on rare and high-impact genes shared by at least 3 unrelated patients from each family and selected 16 gene variants. Through combined data analysis from MCODE with gene ontology and KEGG pathways, a short list of eight candidate genes (ATM, EP300, LAMA1, LAMC2, TNNI3, MYLK, COL11A2, and LAMB3) was created. The impact of the 24 selected genes on survival was analyzed using the TCGA data resulting in a selection of five candidate genes (EP300, KMT2C, RHPN2, HSPG2, and CCR3) that showed a significant association with survival. (4) Conclusions: We identify novel candidate genes predisposed to HBOC that need to be validated in larger cohorts and investigated by analyzing the co-segregation of selected variants in affected families and the locus-specific loss of heterozygosity to highlight their relevance for HBOC risk.
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Affiliation(s)
- Dorra BenAyed-Guerfali
- Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, Sfax 3038, Tunisia; (D.B.-G.); (C.K.); (N.A.-B.); (W.A.)
| | - Chamseddine Kifagi
- Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, Sfax 3038, Tunisia; (D.B.-G.); (C.K.); (N.A.-B.); (W.A.)
| | - Wala BenKridis-Rejeb
- Department of Medical Oncology, Habib Bourguiba Hospital, Sfax 3002, Tunisia; (W.B.-R.); (A.K.)
| | - Nihel Ammous-Boukhris
- Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, Sfax 3038, Tunisia; (D.B.-G.); (C.K.); (N.A.-B.); (W.A.)
| | - Wajdi Ayedi
- Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, Sfax 3038, Tunisia; (D.B.-G.); (C.K.); (N.A.-B.); (W.A.)
| | - Afef Khanfir
- Department of Medical Oncology, Habib Bourguiba Hospital, Sfax 3002, Tunisia; (W.B.-R.); (A.K.)
| | - Jamel Daoud
- Department of Radiotherapy, Habib Bourguiba Hospital, Sfax 3002, Tunisia;
| | - Raja Mokdad-Gargouri
- Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, Sfax 3038, Tunisia; (D.B.-G.); (C.K.); (N.A.-B.); (W.A.)
- Correspondence: ; Tel./Fax: +216-748-744-49
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Hisamoto T, Suga H, Omori I, Mizuno Y, Oka K, Boki H, Takahashi‐Shishido N, Oka T, Miyagaki T, Sugaya M, Sato S. Decreased keratinocyte
Proline‐Rich
protein expression in cutaneous T‐cell lymphoma. JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY 2022. [DOI: 10.1002/cia2.12240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Teruyoshi Hisamoto
- Department of Dermatology University of Tokyo Graduate School of Medicine Tokyo Japan
| | - Hiraku Suga
- Department of Dermatology University of Tokyo Graduate School of Medicine Tokyo Japan
| | - Issey Omori
- Department of Dermatology University of Tokyo Graduate School of Medicine Tokyo Japan
| | - Yuka Mizuno
- Department of Dermatology University of Tokyo Graduate School of Medicine Tokyo Japan
| | - Kenta Oka
- Department of Dermatology University of Tokyo Graduate School of Medicine Tokyo Japan
| | - Hikari Boki
- Department of Dermatology University of Tokyo Graduate School of Medicine Tokyo Japan
| | | | - Tomonori Oka
- Department of Dermatology University of Tokyo Graduate School of Medicine Tokyo Japan
| | - Tomomitsu Miyagaki
- Departments of Dermatology St. Marianna University School of Medicine Kanagawa Japan
| | - Makoto Sugaya
- Department of Dermatology International University of Health and Welfare Chiba Japan
| | - Shinichi Sato
- Department of Dermatology University of Tokyo Graduate School of Medicine Tokyo Japan
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Dai M, Zhu X, Yu J, Yuan J, Zhu Y, Bao Y, Yong X. CCR3 gene knockout in bone marrow cells ameliorates combined allergic rhinitis and asthma syndrome (CARAS) by reducing airway inflammatory cell infiltration and Th2 cytokines expression in mice model. Int Immunopharmacol 2022; 104:108509. [PMID: 34998035 DOI: 10.1016/j.intimp.2021.108509] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 12/17/2021] [Accepted: 12/28/2021] [Indexed: 12/15/2022]
Abstract
The present study aims to investigate the effects of CCR3 gene knockout in bone marrow cells (CCR3-KO) on the mouse model of combined allergic rhinitis and asthma syndrome (CARAS). It was found that CCR3-KO significantly reduced eosinophil (EOS) migration into the nasal (NALF) and bronchoalveolar (BALF) cavities of mice, and decreased Th2 cytokines (such as, IL-4, IL-5 and IL-13) levels in nasal mucosa and lung tissues. In addition, histological analysis showed that the damage degree of nasal mucosa structure in ovalbumin (OVA) modulated CCR3-KO mice was significantly less than that in OVA modulated Wild type (WT) mice, with reduced inflammatory cell infiltration and nasal mucus secretion. The infiltration of inflammatory cells in lung tissue was significantly reduced, and the proliferation of lung smooth muscle layer and extracellular matrix (ECM) production were decreased. Symptom analysis showed that CCR3-KO can reduced allergic rhinitis (AR) signals as nose scratching and sneezing. It was also found CCR3-KO reduce OVA-induced weight loss. The results showed that CCR3-KO could reduce the symptoms of allergic inflammation in CARAS mice by reducing airway inflammatory cell infiltration and down-regulating the expression of Th2 cytokines, and CCR3 gene could be used as a target gene for the treatment of CARAS.
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Affiliation(s)
- MeiNa Dai
- The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang City, Jiangxi Province, 330000, China.
| | - XinHua Zhu
- The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang City, Jiangxi Province, 330000, China.
| | - Juan Yu
- The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang City, Jiangxi Province, 330000, China.
| | - JiaSheng Yuan
- The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang City, Jiangxi Province, 330000, China.
| | - Yv Zhu
- The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang City, Jiangxi Province, 330000, China.
| | - YouWei Bao
- The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang City, Jiangxi Province, 330000, China.
| | - XiaoZhuang Yong
- Institute of Translational Medicine, Nanchang University, 1299 Xuefu Avenue, Honggutan New District, Nanchang City, Jiangxi Province, 330000, China.
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11
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Beksaç B, Gleason L, Baik S, Ringe JM, Porcu P, Nikbakht N. Dermal fibroblasts promote cancer cell proliferation and exhibit fibronectin overexpression in early mycosis fungoides. J Dermatol Sci 2022; 106:53-60. [PMID: 35331619 PMCID: PMC9133159 DOI: 10.1016/j.jdermsci.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 02/07/2022] [Accepted: 03/13/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Mycosis fungoides (MF) is caused by proliferation of malignant T-cells in the skin and may progress to involve blood, lymph nodes, and viscera. While the skin microenvironment is essential for the initiation and progression of MF in early stages, little is known about the impact of skin stroma on the growth and survival of malignant lymphocytes. OBJECTIVE We investigated the effect of dermal fibroblasts and their product, fibronectin, on the survival and proliferation of malignant MF cells. METHODS Fibroblasts and malignant MF CD4 T-cells were isolated from skin of patients with early-stage MF. Fibroblast-lymphocyte co-culture experiments and lymphocyte cultures on fibronectin-coated plates were established utilizing the cells derived from lesional skin, blood, and MF cell lines. The survival and proliferation rates of lymphocytes were assessed via Annexin V and carboxyfluorescein succinimidyl ester assays respectively. Additionally, integrin and fibronectin expressions in MF skin were assessed via immunofluorescence. RESULTS We found that dermal fibroblasts increased the proliferation rates of MF cells, but not normal skin or blood CD4 T-cells. However, fibroblasts did not rescue MF cells from apoptosis in co-cultures. In MF skin, we found an overexpression of a fibronectin isoform not normally found in healthy skin. MF cells expressed fibronectin-binding integrins and adhered to fibronectin but did not exhibit adhesion-mediated survival via fibronectin-integrin interactions. CONCLUSION Overall, our results suggest a direct role for fibroblasts, independent of fibronectin-mediated adhesion, in promoting MF cell proliferation. These findings have implications in understanding and targeting the malignant skin stromal microenvironment in cutaneous lymphomas.
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Liu Z, Wu X, Hwang ST, Liu J. The Role of Tumor Microenvironment in Mycosis Fungoides and Sézary Syndrome. Ann Dermatol 2021; 33:487-496. [PMID: 34858000 PMCID: PMC8577908 DOI: 10.5021/ad.2021.33.6.487] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 03/21/2021] [Accepted: 04/06/2021] [Indexed: 11/25/2022] Open
Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphomas (CTCLs). Most cases of MF display an indolent course during its early stage. However, in some patients, it can progress to the tumor stage with potential systematic involvement and a poor prognosis. SS is defined as an erythrodermic CTCL with leukemic involvements. The pathogenesis of MF and SS is still not fully understood, but recent data have found that the development of MF and SS is related to genetic alterations and possibly to environmental influences. In CTCL, many components interacting with tumor cells, such as tumor-associated macrophages, fibroblasts, dendritic cells, mast cells, and myeloid-derived suppressor cells, as well as with chemokines, cytokines and other key players, establish the tumor microenvironment (TME). In turn, the TME regulates tumor cell migration and proliferation directly and indirectly and may play a critical role in the progression of MF and SS. The TME of MF and SS appear to show features of a Th2 phenotype, thus dampening tumor-related immune responses. Recently, several studies have been published on the immunological characteristics of MF and SS, but a full understanding of the CTCL-related TME remains to be determined. This review focuses on the role of the TME in MF and SS, aiming to further demonstrate the pathogenesis of the disease and to provide new ideas for potential treatments targeted at the microenvironment components of the tumor.
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Affiliation(s)
- Zhaorui Liu
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Xuesong Wu
- Department of Dermatology, School of Medicine, University of California Davis, Sacramento, CA, United States
| | - Sam T Hwang
- Department of Dermatology, School of Medicine, University of California Davis, Sacramento, CA, United States
| | - Jie Liu
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
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13
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Malignant and Benign T Cells Constituting Cutaneous T-Cell Lymphoma. Int J Mol Sci 2021; 22:ijms222312933. [PMID: 34884736 PMCID: PMC8657644 DOI: 10.3390/ijms222312933] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/22/2021] [Accepted: 11/26/2021] [Indexed: 02/06/2023] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphoma, including various clinical manifestations, such as mycosis fungoides (MF) and Sézary syndrome (SS). CTCL mostly develops from CD4 T cells with the skin-tropic memory phenotype. Malignant T cells in MF lesions show the phenotype of skin resident memory T cells (TRM), which reside in the peripheral tissues for long periods and do not recirculate. On the other hand, malignant T cells in SS represent the phenotype of central memory T cells (TCM), which are characterized by recirculation to and from the blood and lymphoid tissues. The kinetics and the functional characteristics of malignant cells in CTCL are still unclear due, in part, to the fact that both the malignant cells and the T cells exerting anti-tumor activity possess the same characteristics as T cells. Capturing the features of both the malignant and the benign T cells is necessary for understanding the pathogenesis of CTCL and would lead to new therapeutic strategies specifically targeting the skin malignant T cells or benign T cells.
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14
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De Zutter A, Van Damme J, Struyf S. The Role of Post-Translational Modifications of Chemokines by CD26 in Cancer. Cancers (Basel) 2021; 13:cancers13174247. [PMID: 34503058 PMCID: PMC8428238 DOI: 10.3390/cancers13174247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/04/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer. Both tumor-promoting and -impeding roles have been ascribed to chemokines, which they exert in a direct or indirect manner. An important post-translational modification that regulates chemokine activity is the NH2-terminal truncation by peptidases. CD26 is a dipeptidyl peptidase (DPPIV), which typically clips a NH2-terminal dipeptide from the chemokine. With a certain degree of selectivity in terms of chemokine substrate, CD26 only recognizes chemokines with a penultimate proline or alanine. Chemokines can be protected against CD26 recognition by specific amino acid residues within the chemokine structure, by oligomerization or by binding to cellular glycosaminoglycans (GAGs). Upon truncation, the binding affinity for receptors and GAGs is altered, which influences chemokine function. The consequences of CD26-mediated clipping vary, as unchanged, enhanced, and reduced activities are reported. In tumors, CD26 most likely has the most profound effect on CXCL12 and the interferon (IFN)-inducible CXCR3 ligands, which are converted into receptor antagonists upon truncation. Depending on the tumor type, expression of CD26 is upregulated or downregulated and often results in the preferential generation of the chemokine isoform most favorable for tumor progression. Considering the tight relationship between chemokine sequence and chemokine binding specificity, molecules with the appropriate characteristics can be chemically engineered to provide innovative therapeutic strategies in a cancer setting.
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Radonjic-Hoesli S, Brüggen MC, Feldmeyer L, Simon HU, Simon D. Eosinophils in skin diseases. Semin Immunopathol 2021; 43:393-409. [PMID: 34097126 PMCID: PMC8241748 DOI: 10.1007/s00281-021-00868-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/06/2021] [Indexed: 02/06/2023]
Abstract
Eosinophil infiltration is a common finding in a broad spectrum of skin diseases, despite the fact that the skin is devoid of eosinophils under physiologic conditions. Although cutaneous eosinophilia is reactive, cytokine-mediated in most cases, diseases with an intrinsic mutation-mediated clonal expansion of eosinophils can also manifest on the skin. As eosinophils are involved in host defense, regulate immune responses, generate pruritus, induce remodeling and fibrosis, and can cause tissue damage, they have the capacity to actively contribute to the pathogenesis of diseases. Recent research provided deeper insights in the mechanisms, e.g., bacterial and viral clearance, blister formation, recruitment of cytotoxic T cells, and generation of pruritus, by which eosinophils might come into action. This review aims at providing an overview on the clinical presentations of eosinophil-associated dermatoses and the current understanding of their pathogenic role in these diseases. Further, we discuss the effects of therapies targeting eosinophils.
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Affiliation(s)
- Susanne Radonjic-Hoesli
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marie-Charlotte Brüggen
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
- Department of Dermatology, Hochgebirgsklinik Davos, Davos, Switzerland
| | - Laurence Feldmeyer
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Department of Clinical Immunology and Allergology, Sechenov University, Moscow, Russia
- Laboratory of Molecular Immunology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Dagmar Simon
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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16
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Mehdi SJ, Moerman-Herzog A, Wong HK. Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma. BMC Cancer 2021; 21:492. [PMID: 33941102 PMCID: PMC8091512 DOI: 10.1186/s12885-021-08142-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 04/02/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin. The role of the skin microenvironment in MF development is unclear, but recent findings in a variety of cancers have highlighted the role of stromal fibroblasts in promoting or inhibiting tumorigenesis. Stromal fibroblasts are an important part of the cutaneous tumor microenvironment (TME) in MF. Here we describe studies into the interaction of TME-fibroblasts and malignant T cells to gain insight into their role in CTCL. METHODS Skin from normal (n = 3) and MF patients (n = 3) were analyzed for FAPα by immunohistochemistry. MyLa is a CTCL cell line that retains expression of biomarkers TWIST1 and TOX that are frequently detected in CTCL patients. MyLa cells were cultured in the presence or absence of normal or MF skin derived fibroblasts for 5 days, trypsinized to detached MyL a cells, and gene expression analyzed by RT-PCR for MF biomarkers (TWIST1 and TOX), Th1 markers (IFNG, TBX21), Th2 markers (GATA3, IL16), and proliferation marker (MKI67). Purified fibroblasts were assayed for VIM and ACTA2 gene expression. Cellular senescence assay was performed to assess senescence. RESULTS MF skin fibroblast showed increased expression of FAP-α with increasing stage compared to normal. Normal fibroblasts co-cultured with MyLa cells suppressed expression of TWIST1 (p < 0.0006), and TOX (p < 0.03), GATA3 (p < 0.02) and IL16 (p < 0.03), and increased expression of IFNG (p < 0.03) and TBX21 (p < 0.03) in MyLa cells. In contrast, MyLa cells cultured with MF fibroblasts retained high expression of TWIST1, TOX and GATA3. MF fibroblasts co-culture with MyLa cells increased expression of IL16 (p < 0.01) and IL4 (p < 0.02), and suppressed IFNG and TBX21 in MyLa cells. Furthermore, expression of MKI67 in MyLa cells was suppressed by normal fibroblasts compared to MF fibroblasts. CONCLUSION Skin fibroblasts represent important components of the TME in MF. In co-culture model, normal and MF fibroblasts have differential influence on T-cell phenotype in modulating expression of Th1 cytokine and CTCL biomarker genes to reveal distinct roles with implications in MF progression.
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Affiliation(s)
- Syed Jafar Mehdi
- Department of Dermatology, University of Arkansas for Medical Sciences, 4301 West Markham St, #576, Little Rock, AR, 72205, USA
| | - Andrea Moerman-Herzog
- Department of Dermatology, University of Arkansas for Medical Sciences, 4301 West Markham St, #576, Little Rock, AR, 72205, USA
| | - Henry K Wong
- Department of Dermatology, University of Arkansas for Medical Sciences, 4301 West Markham St, #576, Little Rock, AR, 72205, USA.
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Cancer-Associated Fibroblasts Play an Important Role in Early-Stage Mycosis Fungoides. J Invest Dermatol 2021; 141:479-480. [PMID: 33618804 DOI: 10.1016/j.jid.2020.08.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/07/2020] [Accepted: 08/07/2020] [Indexed: 02/07/2023]
Abstract
Research in cutaneous T-cell lymphoma has widened from the malignant T cell itself to the tumor microenvironment. In this issue of the Journal of Investigative Dermatology, Aronovich et al. (2020) report the presence of cancer-associated fibroblasts (CAFs) in mycosis fungoides (MFs). They show that CAFs are abundant in early-stage MF and that they differ from normal fibroblasts. Moreover, CAFs are described to promote MF by increasing the motility and chemoresistance of malignant T cells. Thus, targeting CAFs in MF may be of therapeutic value.
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18
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Myeloid-derived suppressor cells promote lung cancer metastasis by CCL11 to activate ERK and AKT signaling and induce epithelial-mesenchymal transition in tumor cells. Oncogene 2021; 40:1476-1489. [PMID: 33452453 DOI: 10.1038/s41388-020-01605-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 12/01/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune activities and facilitate cancer progression. Although the concept of immunosuppressive MDSCs is well established, the mechanism that MDSCs regulate non-small cell lung cancer (NSCLC) progression through the paracrine signals is still lacking. Here, we reported that the infiltration of MDSCs within NSCLC tissues was associated with the progression of cancer status, and was positively correlated with the Patient-derived xenograft model establishment, and poor patient prognosis. Intratumoral MDSCs directly promoted NSCLC metastasis and highly expressed chemokines that promote NSCLC cells invasion, including CCL11. CCL11 was capable of activating the AKT and ERK signaling pathways to promote NSCLC metastasis through the epithelial-mesenchymal transition (EMT) process. Moreover, high expression of CCL11 was associated with a poor prognosis in lung cancer as well as other types of cancer. Our findings underscore that MDSCs produce CCL11 to promote NSCLC metastasis via activation of ERK and AKT signaling and induction of EMT, suggesting that the MDSCs-CCL11-ERK/AKT-EMT axis contains potential targets for NSCLC metastasis treatment.
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Stolearenco V, Namini MRJ, Hasselager SS, Gluud M, Buus TB, Willerslev-Olsen A, Ødum N, Krejsgaard T. Cellular Interactions and Inflammation in the Pathogenesis of Cutaneous T-Cell Lymphoma. Front Cell Dev Biol 2020; 8:851. [PMID: 33015047 PMCID: PMC7498821 DOI: 10.3389/fcell.2020.00851] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/10/2020] [Indexed: 12/17/2022] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) comprises a group of lymphoproliferative diseases characterized by the accumulation of malignant T cells in chronically inflamed skin lesions. In early stages, the disease presents as skin patches or plaques covering a limited area of the skin and normally follows an indolent course. However, in a subset of patients the cutaneous lesions develop into tumors and the malignant T cells may spread to the lymphatic system, blood and internal organs with fatal consequences. Despite intensive research, the mechanisms driving disease progression remain incompletely understood. While most studies have focused on cancer cell-intrinsic oncogenesis, such as genetic and epigenetic events driving malignant transformation and disease progression, an increasing body of evidence shows that the interplay between malignant T cells and non-malignant cells plays a crucial role. Here, we outline some of the emerging mechanisms by which tumor, stromal and epidermal interactions may contribute to the progression of CTCL with particular emphasis on the crosstalk between fibroblasts, keratinocytes and malignant T cells.
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Affiliation(s)
- Veronica Stolearenco
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Martin R J Namini
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Siri S Hasselager
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Maria Gluud
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Terkild B Buus
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Andreas Willerslev-Olsen
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Niels Ødum
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Thorbjørn Krejsgaard
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
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20
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Siddiqui S, Jaiswal R, Hashmi GS. Quantitative analysis of tumor-associated tissue eosinophils and tumor-associated blood eosinophils in oral squamous cell carcinoma. J Oral Maxillofac Pathol 2020; 24:131-137. [PMID: 32508461 PMCID: PMC7269303 DOI: 10.4103/jomfp.jomfp_70_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 01/14/2020] [Accepted: 02/07/2020] [Indexed: 01/21/2023] Open
Abstract
Background: Stromal response to cancer is usually characterized by intense lymphoplasmacytic infiltrate. However, recently, the attention has shifted to tumor-associated tissue eosinophils (TATE). Tumor-associated blood eosinophils (TABE) are rare in solid cancers; however, carcinoma of the head and neck shows its prevalence. Aim: The aim of the study was to investigate the prevalence and relationship of tissue and blood eosinophils in various grades of oral cancer. The purpose of the article is to emphasize the possible clinical and biological significance of eosinophils in patients of oral squamous cell carcinoma (OSCC) so that appropriate therapeutic strategies can be devised accordingly. Study Design: Thirty histologically confirmed cases of oral squamous cell carcinoma were divided into well, moderate and poorly differentiated carcinoma. Eosinophilic infiltration in the tissue was graded as low, moderate and massive TATE. The number of eosinophils per 100 WBCs was taken as the differential eosinophil count. Blood eosinophilia (BE) >6% was considered to be TABE. Materials and Methods: Hematoxylin and eosin-stained tissue sections at 5 μ were evaluated. Prolonged staining in dilute 0.05% aqueous eosin demonstrated eosinophils selectively. Blood smears were stained by Leishman stain. Statistical Analysis: Student's t-test, Chi-square test, ANOVA, Newman–Keuls Multiple Comparison Test and Karl Pearson correlation coefficient® method were used. Results: The mean TATE value was highest in poorly differentiated carcinoma. TABE was seen only in a few cases and was associated mostly with poorly differentiated OSCC. Conclusion: There was a statistically significant correlation between TATE and histological grades of OSCC. Eosinophilia of the peripheral blood is an adverse sign in patients with carcinoma.
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Affiliation(s)
- Safia Siddiqui
- Department of Oral Pathology and Microbiology, Sardar Patel Post Graduate Institute of Dental and Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Rohit Jaiswal
- Department of Oral Pathology and Microbiology, Sardar Patel Post Graduate Institute of Dental and Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Ghulam Sarwar Hashmi
- Department of Oral and Maxillofacial Surgery, ZA Dental College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
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21
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Abstract
Cutaneous T-cell lymphomas (CTCLs) comprise a heterogeneous group of extranodal non-Hodgkin lymphomas involving primarily the skin and mycosis fungoides is its most frequent entity. Whereas most patients show an indolent course in early disease (clinical stages IA to IIA), some patients progress to advanced disease (stage IIB or higher), and the 5-year survival rate is unfavorable: only 47% (stage IIB) to 18% (stage IVB). Except for allogeneic stem cell transplantation, there is currently no cure for CTCL and thus treatment approaches are palliative, focusing on patients’ health-related quality of life. Our aims were to review the current understanding of the pathogenesis of CTCL, such as the shift in overall immune skewing with progressive disease and the challenges of making a timely diagnosis in early-stage disease because of the lack of reliable positive markers for routine diagnostics, and to discuss established and potential treatment modalities such as immunotherapy and novel targeted therapeutics.
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Affiliation(s)
- Patrick M Brunner
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Austria
| | - Constanze Jonak
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Austria
| | - Robert Knobler
- Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Austria
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Vieyra-Garcia P, Fink-Puches R, Porkert S, Lang R, Pöchlauer S, Ratzinger G, Tanew A, Selhofer S, Paul-Gunther S, Hofer A, Gruber-Wackernagel A, Legat F, Patra V, Quehenberger F, Cerroni L, Clark R, Wolf P. Evaluation of Low-Dose, Low-Frequency Oral Psoralen-UV-A Treatment With or Without Maintenance on Early-Stage Mycosis Fungoides: A Randomized Clinical Trial. JAMA Dermatol 2020; 155:538-547. [PMID: 30892603 DOI: 10.1001/jamadermatol.2018.5905] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Importance Psoralen-UV-A (PUVA) photochemotherapy is standard first-line treatment for skin-limited, early-stage mycosis fungoides capable of producing high initial complete response (CR) rates. However, much remains unknown about PUVA's therapeutic mechanisms, optimal duration and frequency of treatment, dose escalation, or use as maintenance therapy. Objectives To evaluate low-dose, low-frequency PUVA, and whether maintenance treatment extends disease-free remission in patients with mycosis fungoides. Design, Setting, and Participants This prospective randomized clinical trial with defined PUVA dosing regimen was carried out in 5 centers (Graz, Vienna, Hietzing, Innsbruck, and Salzburg) across Austria. Patients with stage IA to IIA mycosis fungoides (n = 27) were enrolled in the study beginning March 13, 2013, with the last patient enrolled March 21, 2016. These patients were treated with oral 8-methoxypsoralen followed by UV-A exposure 2 times per week for 12 to 24 weeks until CR. Patients with CR were randomized to PUVA maintenance for 9 months (14 total exposures) or no maintenance. The study was conducted from April 27, 2012, to July 27, 2018. Data analysis of the primary end point was of the intention-to-treat population, and the secondary end point analysis was of the evaluable population. Main Outcomes and Measures Efficacy of the PUVA regimen was determined by the rate of CR as defined by a modified severity-weighted assessment tool (mSWAT) score reduction to 0. Levels of proinflammatory molecules in serum and histologic features and percentage of clonal T cells in skin were assessed to search for biomarkers of clinical response. Results In 27 patients with mycosis fungoides, 19 (70%) were male with mean (range) age 61 (30-80) years. At baseline, patients with CR had a mean (range) mSWAT score of 18.6 (1-66) compared with 16.8 (3-46) in patients with partial response. The 12- to 24-week PUVA induction regimen reduced the mSWAT score in all patients and led to CR in 19 (70%) of 27 patients and a low mean cumulative UV-A dose of 78.5 J/cm2. The subsequent standardized 9-month PUVA maintenance phase prolonged median (range) disease-free remission from 4 (1-20) months to 15 (1-54) months (P = .02). High density of histologic infiltrate and high percentage of clonal TCR sequences in skin biopsy specimens at baseline were inversely associated with therapeutic response. No severe adverse effects were seen during the PUVA induction or maintenance phase. Conclusions and Relevance This proof-of-concept study identifies potential biomarkers for therapeutic response to PUVA in mycosis fungoides; it also demonstrates that low-dose, low-frequency PUVA appears to be highly effective, and maintenance treatment may extend disease-free remission. Trial Registration ClinicalTrials.gov identifier: NCT01686594.
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Affiliation(s)
- Pablo Vieyra-Garcia
- Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Regina Fink-Puches
- Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Stefanie Porkert
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Roland Lang
- Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | | | - Gudrun Ratzinger
- Department of Dermatology and Venerology, Medical University of Innsbruck, Innsbruck, Austria
| | - Adrian Tanew
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Sylvia Selhofer
- Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | | | - Angelika Hofer
- Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Alexandra Gruber-Wackernagel
- Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Franz Legat
- Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Vijaykumar Patra
- Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Franz Quehenberger
- Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
| | - Lorenzo Cerroni
- Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Rachael Clark
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Peter Wolf
- Research Unit for Photodermatology, Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
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Abstract
PURPOSE OF REVIEW Novel immunotherapies such as checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells are leading to promising responses when treating solid tumors and hematological malignancies. T cell neoplasms include leukemia and lymphomas that are derived from T cells and overall are characterized by poor clinical outcomes. This review describes the rational and preliminary results of immunotherapy for patients with T cell lymphoma and leukemia. RECENT FINDINGS For T cell neoplasms, despite significant research effort, only few agents, such as monoclonal antibodies and allogeneic stem cell transplantation, showed some clinical activity. One of the major hurdles to targeting T cell neoplasms is that activation or elimination of T cells, either normal or neoplastic, can cause significant toxicity. A need to develop novel safe and effective immunotherapies for T cell neoplasms exists. In this review, we will discuss the rationale for immunotherapy of T cell leukemia and lymphoma and present the most recent therapeutic approaches.
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Pilot trial of ibrutinib in patients with relapsed or refractory T-cell lymphoma. Blood Adv 2019; 2:871-876. [PMID: 29669753 DOI: 10.1182/bloodadvances.2017011916] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 01/09/2018] [Indexed: 12/24/2022] Open
Abstract
Ibrutinib has previously been shown to inhibit Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK), which mediate B-cell and T-cell receptor signaling, respectively. BTK inhibition with ibrutinib has demonstrated impressive clinical responses in a variety of B-cell malignancies. Whether ibrutinib inhibition of ITK can lead to clinical response in T-cell malignancies is unknown. We hypothesized that ibrutinib-mediated ITK inhibition in T-cell lymphoma would result in decreased signaling through the T-cell receptor pathway and promote antitumor immune response by driving selective cytotoxic Th1 CD4 effector T-cell differentiation. This pilot clinical trial evaluated 2 dose levels of ibrutinib: 560 and 840 mg orally daily. Fourteen patients with relapsed, refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma were enrolled. Both dose levels were safe and well tolerated, and no dose-limiting toxicities were observed. One patient achieved a partial response (overall response rate, 8% [1/13]). ITK occupancy studies demonstrated a mean occupancy of 50% (range, 15%-80%). Higher ITK occupancy of more than 50% correlated with higher serum levels of tumor necrosis factor-α and interferon-γ and favored a Th1 phenotype. Our data suggest that ibrutinib inhibition of ITK has limited clinical activity in T-cell lymphoma. This study is registered at www.clinicaltrials.gov as #NCT02309580.
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25
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Broglie L, Gershan J, Burke MJ. Checkpoint inhibition of PD-L1 and CTLA-4 in a child with refractory acute leukemia. Int J Hematol Oncol 2019; 8:IJH10. [PMID: 30863527 PMCID: PMC6410023 DOI: 10.2217/ijh-2018-0009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 12/11/2018] [Indexed: 01/22/2023] Open
Abstract
Children with multiple relapsed or refractory leukemia have dismal survival. Research has identified engagement of immune checkpoint receptors (e.g., PD-1, PD-L1 and CTLA-4) as a mechanism for treatment resistance. For adult cancer, inhibitors of PD-1 (nivolumab) and CTLA-4 (ipilimumab) have shown promise with response rates ranging from 7 to 40%. In vitro studies using acute myeloid leukemia cell lines have shown that acute myeloid leukemia blasts may similarly utilize the PD-1/PD-L1 axis to evade an anticancer immune response. We report the first case of a pediatric patient with multiple relapsed/refractory leukemia treated with nivolumab, ipilimumab and 5-azacytidine who tolerated therapy with brief improvement of symptoms.
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Affiliation(s)
- Larisa Broglie
- Department of Pediatrics, Division of Hematology/Oncology & Blood & Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, 53226, USA,Department of Pediatric, Division of Hematology/Oncology & Blood & Marrow Transplantation, Columbia University Medical Center, New York, NY, 10027, USA
| | - Jill Gershan
- Department of Pediatrics, Division of Hematology/Oncology & Blood & Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Michael J Burke
- Department of Pediatrics, Division of Hematology/Oncology & Blood & Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI, 53226, USA,*Author for correspondence: Tel.: +1 414 955 4170; Fax: +1 414 955 6543;
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Serrano L, Martinez-Escala ME, Zhou XA, Guitart J. Pruritus in Cutaneous T-Cell Lymphoma and Its Management. Dermatol Clin 2018; 36:245-258. [DOI: 10.1016/j.det.2018.02.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Jaque A, Mereniuk A, Sade S, Lansang P, Imrie K, Shear NH. Eosinophils in the skin-a red herring masking lymphoma: a case series. SAGE Open Med Case Rep 2018; 6:2050313X18773127. [PMID: 29899986 PMCID: PMC5985601 DOI: 10.1177/2050313x18773127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Eosinophilia, both peripheral and in cutaneous tissue, is not a typical finding in mycosis fungoides; in fact, when faced with a lymphoeosinophilic infiltrate, mycosis fungoides is often not part of initial differential considerations. However, eosinophilia has been described in certain subtypes of mycosis fungoides, namely, in folliculotropic mycosis fungoides. We describe three challenging cases of folliculotropic mycosis fungoides presenting with varied clinical morphologies and a dense lymphoeosinophilic infiltrate and/or severe hypereosinophilia that obscured the final diagnosis for years. Only after treatment of the eosinophilia were the underlying atypical lymphocytes more apparent on histology and a correct diagnosis made. Thus, when characteristic features of mycosis fungoides are subtle, eosinophils can act as a red herring in terms of clinico-pathologic correlation and may prevent early and accurate diagnosis of mycosis fungoides. We suggest that further studies are needed to evaluate whether treatments to reduce eosinophilia, once other causes have been excluded, may help clear the confounding reactive inflammatory infiltrate and facilitate the diagnosis of mycosis fungoides.
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Affiliation(s)
- Alejandra Jaque
- University of Toronto and Department of Medicine, Sunnybrook Hospital, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Alexandra Mereniuk
- University of Toronto and Department of Medicine, Sunnybrook Hospital, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Shachar Sade
- University of Toronto and Department of Pathology, Sunnybrook Hospital, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Perla Lansang
- University of Toronto and Department of Medicine, Sunnybrook Hospital, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Kevin Imrie
- University of Toronto and Department of Medicine, Sunnybrook Hospital, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Neil H Shear
- University of Toronto and Department of Medicine, Sunnybrook Hospital, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
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Fujii K. New Therapies and Immunological Findings in Cutaneous T-Cell Lymphoma. Front Oncol 2018; 8:198. [PMID: 29915722 PMCID: PMC5994426 DOI: 10.3389/fonc.2018.00198] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 05/17/2018] [Indexed: 01/08/2023] Open
Abstract
Primary cutaneous lymphomas comprise a group of lymphatic malignancies that occur primarily in the skin. They represent the second most common form of extranodal non-Hodgkin’s lymphoma and are characterized by heterogeneous clinical, histological, immunological, and molecular features. The most common type is mycosis fungoides and its leukemic variant, Sézary syndrome. Both diseases are considered T-helper cell type 2 (Th2) diseases. Not only the tumor cells but also the tumor microenvironment can promote Th2 differentiation, which is beneficial for the tumor cells because a Th1 environment enhances antitumor immune responses. This Th2-dominant milieu also underlies the infectious susceptibility of the patients. Many components, such as tumor-associated macrophages, cancer-associated fibroblasts, and dendritic cells, as well as humoral factors, such as chemokines and cytokines, establish the tumor microenvironment and can modify tumor cell migration and proliferation. Multiagent chemotherapy often induces immunosuppression, resulting in an increased risk of serious infection and poor tolerance. Therefore, overtreatment should be avoided for these types of lymphomas. Interferons have been shown to increase the time to next treatment to a greater degree than has chemotherapy. The pathogenesis and prognosis of cutaneous T-cell lymphoma (CTCL) differ markedly among the subtypes. In some aggressive subtypes of CTCLs, such as primary cutaneous gamma/delta T-cell lymphoma and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, hematopoietic stem cell transplantation should be considered, whereas overtreatment should be avoided with other, favorable subtypes. Therefore, a solid understanding of the pathogenesis and immunological background of cutaneous lymphoma is required to better treat patients who are inflicted with this disease. This review summarizes the current knowledge in the field to attempt to achieve this objective.
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Affiliation(s)
- Kazuyasu Fujii
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Intratumoral expression of CCR3 in breast cancer is associated with improved relapse-free survival in luminal-like disease. Oncotarget 2017; 7:28570-8. [PMID: 27086913 PMCID: PMC5053746 DOI: 10.18632/oncotarget.8680] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 03/28/2016] [Indexed: 01/22/2023] Open
Abstract
PURPOSE The association chemokine receptor CCR3 with breast cancer subtypes and relapse-free survival is unknown. RESULTS The overall expression (either intratumoral or peritumoral) of CCR3 was not associated with tumor size, lymph node status, age, and subtype. When we confined the analysis in samples without peritumoral stromal CCR3 expression, intratumoral expression of CCR3 was associated with breast cancer subtype (P=0.04). Tumors with high expression of CCR3 were more likely to be luminal-like rather than TNBC or HER2-enriched cancers. Moreover, high mRNA expression of CCR3 was related with improved relapse-free survival in luminal-A/B (P<0.001). The subsequent sensitivity analysis using the systemically untreated patients confirmed that higher mRNA expression of CCR3 was a robust prognostic factor for luminal-A (P=0.0025) and luminal-B (P=0.088), but not for HER2-enriched (P=0.21) and TNBC (P=0.86). In the independent cohort, the positive association between increased expression of CCR3 and improved distant relapse-free survival was also observed. METHODS We determined the expression level of CCR3 in 150 cases with breast cancer by using immunohistochemistry (IHC) assay, for both intratumoral and peritumoral stroma, and investigated the effect of CCR3 expression on relapse-free survival according to subtype using cases from publicly available datasets, in the whole group (N=3557) and in the patients without adjuvant systemic treatment (N=1005), respectively. Moreover, the survival outcomes were validated in another independent cohort including 508 breast cancer patients treated with neoadjuvant chemotherapy. CONCLUSIONS Our data indicate that intratumoral expression of CCR3 in breast cancer is associated with improved relapse-free survival in patients with luminal-like disease.
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Pearson DR, Fujita M, High WA. Fulminant Mycosis Fungoides with Tissue Eosinophilia: A Unique Presentation of Two Cases with Acro-Periorbital Ulceration and An Aggressive Clinical Course. ACTA ACUST UNITED AC 2017; 8. [PMID: 28758048 PMCID: PMC5531183 DOI: 10.4172/2155-9929.1000337] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We describe two unique cases of fulminant mycosis fungoides with remarkably similar and aggressive clinical courses resulting in death. Both cases demonstrated ulcerated palmar and periorbital plaques and marked tissue eosinophilia, which was confirmed by T-cell receptor γ chain gene rearrangement studies to display identical monoclonality at temporally and anatomically distinct sites. Dense eosinophilic infiltrates on biopsy led to misdiagnosis of inflammatory dermatoses in both instances. While mycosis fungoides may be challenging to diagnose histologically, the presence of eosinophils in progressive disease may herald a poor prognosis and should not exclude the diagnosis.
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Affiliation(s)
| | - Mayumi Fujita
- University of Colorado School of Medicine in Aurora, USA
| | - Whitney A High
- University of Colorado School of Medicine in Aurora, USA
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Gregor CE, Foeng J, Comerford I, McColl SR. Chemokine-Driven CD4 + T Cell Homing: New Concepts and Recent Advances. Adv Immunol 2017; 135:119-181. [DOI: 10.1016/bs.ai.2017.03.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Malignant inflammation in cutaneous T-cell lymphoma-a hostile takeover. Semin Immunopathol 2016; 39:269-282. [PMID: 27717961 PMCID: PMC5368200 DOI: 10.1007/s00281-016-0594-9] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 09/14/2016] [Indexed: 01/05/2023]
Abstract
Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL.
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Takahashi N, Sugaya M, Suga H, Oka T, Kawaguchi M, Miyagaki T, Fujita H, Sato S. Thymic Stromal Chemokine TSLP Acts through Th2 Cytokine Production to Induce Cutaneous T-cell Lymphoma. Cancer Res 2016; 76:6241-6252. [PMID: 27634769 DOI: 10.1158/0008-5472.can-16-0992] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 08/24/2016] [Indexed: 11/16/2022]
Abstract
Thymic stromal lymphopoietin (TSLP) activates dendritic cells to induce Th2-mediated inflammation. Periostin, an extracellular matrix protein produced by fibroblasts, induces chronic inflammation by stimulating TSLP production. Recently, a reinforcing cycle linking Th2-type immune responses with periostin-induced keratinocyte activation has been proposed in atopic dermatitis pathogenesis. In this study, we investigated the role of TSLP and periostin in the development of cutaneous T-cell lymphoma (CTCL), where Th2 cytokines and chemokines are also dominant. TSLP and periostin mRNA expression levels were elevated in CTCL lesional skin, both of which correlated with IL4 expression levels. In vitro and ex vivo, IL4 or IL13 stimulated periostin expression by dermal fibroblasts, and fibroblasts from CTCL lesional skin expressed higher levels of periostin than those from control skin. Serum periostin levels of CTCL patients were also significantly higher than those of healthy individuals. Hut78 and MJ, CTCL cell lines, and peripheral blood mononuclear cells from leukemic CTCL patients expressed the TSLP receptor. TSLP induced production of IL4 and IL13 by Hut78 and MJ cells through the activation of STAT5. Moreover, TSLP induced proliferation of CTCL cells both in vitro and in vivo These data suggest that periostin-mediated TSLP production by keratinocytes directly stimulates CTCL tumor cell growth in addition to inducing a Th2-dominant tumor environment in CTCL. Cancer Res; 76(21); 6241-52. ©2016 AACR.
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Affiliation(s)
- Naomi Takahashi
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Makoto Sugaya
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
| | - Hiraku Suga
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tomonori Oka
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Makiko Kawaguchi
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tomomitsu Miyagaki
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Hideki Fujita
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinichi Sato
- Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Yang G, Zhang B, Huang W, Zhang N, Dong F, Jing L, Wang M, Liu Y, Guo C, Pan H, Wei X, Jing C. Systematic review and meta-analysis of the association between IL18RAP rs917997 and CCR3 rs6441961 polymorphisms with celiac disease risks. Expert Rev Gastroenterol Hepatol 2016; 9:1327-38. [PMID: 26289103 DOI: 10.1586/17474124.2015.1075880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES We performed a systematic review and meta-analysis to estimate the polymorphism effects of IL18RAP and CCR3 on celiac disease susceptibility. METHODS PubMed and Web of Science databases were searched (to June 2015) on IL18RAP rs917997 and CCR3 rs6441961 polymorphisms. RESULTS The meta-analysis included 16 and 7 studies for rs917997 and rs6441961, respectively. The minor risk A allele at both rs917997 and rs6441961 carried risks (odds ratios) of 1.24 (95% CI 1.18-1.31) and 1.21 (95% CI 1.12-1.31), respectively. These alleles contributed to increase risks in all celiac disease patients by 5.04 and 6.35%. The estimated lambdas were 0.73 and 0.51, suggesting that an additive model would be the best choice for both gene effects. CONCLUSIONS This meta-analysis provides robust estimates that IL18RAP rs917997 and CCR3 rs6441961 are potential risk factors for celiac disease in European populations. Studies are needed to confirm these findings in different ethnicities.
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Affiliation(s)
- Guang Yang
- a 1 Department of Parasitology, School of Medicine, Jinan University, Guangzhou, China
| | - Baohuan Zhang
- a 1 Department of Parasitology, School of Medicine, Jinan University, Guangzhou, China
| | - Weihuang Huang
- b 2 Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Na Zhang
- b 2 Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Fang Dong
- b 2 Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Lipeng Jing
- b 2 Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Man Wang
- b 2 Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Yang Liu
- b 2 Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Congcong Guo
- b 2 Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
| | - Hongwei Pan
- c 3 Department of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China
| | - Xiangcai Wei
- d 4 Family Planning Research Institute of Guangdong, Guangzhou, China
| | - Chunxia Jing
- b 2 Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, China
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Sézary Syndrome and Atopic Dermatitis: Comparison of Immunological Aspects and Targets. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9717530. [PMID: 27294147 PMCID: PMC4886049 DOI: 10.1155/2016/9717530] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 03/30/2016] [Indexed: 12/27/2022]
Abstract
Sézary syndrome (SS), an aggressive form of erythrodermic pruritic cutaneous T cell lymphoma (CTCL), from an immunological perspective characterized by increased Th2 cytokine levels, elevated serum IgE and impaired cellular immunity. Not only the clinical appearance but also the hallmark immunological characteristics of SS often share striking similarities with acute flares of atopic dermatitis (AD), a common benign chronic inflammatory skin disease. Given the overlap of several immunological features, the application of similar or even identical therapeutic approaches in certain stages of both diseases may come into consideration. The aim of this review is to compare currently accepted immunological aspects and possible therapeutic targets in AD and SS.
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Kubeczko M, Nowara E, Karwasiecka D, Siewior G, Czajka-Francuz P, Chudek J, Wojnar J. C–C motif ligand 11 reduction in CLL patients serum after vitamin D supplementation. Hematology 2016; 21:343-50. [PMID: 26902783 PMCID: PMC4960500 DOI: 10.1080/10245332.2016.1142162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: Vitamin D (VD) deficiency results in a worse prognosis in patients with chronic lymphocytic leukemia (CLL) and may affect the production of cytokines. Nonetheless, there is the lack of studies dealing with VD supplementation and its impact on chemokines in CLL patients. Aim: The primary endpoint of our interventional study was to evaluate the effect of cholecalciferol supplementation on serum chemokines levels in CLL patients. Materials and methods: Eighteen subjects with CLL were enrolled for the study. Six-month-long cholecalciferol supplementation was performed in CLL patients with serum 25-OH-D3 levels below 30 ng/ml. Cytokines levels were assessed at the beginning of the study and after 6 months. Baseline measurements of cytokines were compared to those in apparently healthy controls. Results: Increased levels of CCL2, CCL3, CCL4, CXCL8, CXCL10, TNFα, bFGF, G-CSF, and VEGF were found in CLL patients in comparison with the healthy controls. In the course of the VD supplementation a decrease in serum levels of chemokines CCL11, CCL3, and cytokine PDGF-BB was observed. The decrease of CCL11 was found in CLL patients on VD supplementation solely, whereas the decrease of CCL3 and PDGF-BB was observed in CLL subjects on both chemotherapy and VD supplementation. Conclusion: The VD supplementation may exert beneficial effect on chemokines levels in CLL patients with VD deficiency.
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Affiliation(s)
- Marcin Kubeczko
- Clinical and Experimental Oncology Department, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice 44-400, Poland
- Department of Internal Medicine and Oncological Chemotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-027, Poland
| | - Elżbieta Nowara
- Clinical and Experimental Oncology Department, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice 44-400, Poland
| | - Dobromiła Karwasiecka
- Department of Internal Medicine and Oncological Chemotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-027, Poland
| | - Grażyna Siewior
- Department of Internal Medicine and Oncological Chemotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-027, Poland
| | - Paulina Czajka-Francuz
- Department of Internal Medicine and Oncological Chemotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-027, Poland
| | - Jerzy Chudek
- Department of Internal Medicine and Oncological Chemotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-027, Poland
- Department of Pathophysiology, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-752, Poland
| | - Jerzy Wojnar
- Department of Internal Medicine and Oncological Chemotherapy, School of Medicine in Katowice, Medical University of Silesia, Katowice 40-027, Poland
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Tse E, Kwong YL. T-cell lymphoma: Microenvironment-related biomarkers. Semin Cancer Biol 2015; 34:46-51. [DOI: 10.1016/j.semcancer.2015.06.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 05/27/2015] [Accepted: 06/01/2015] [Indexed: 01/22/2023]
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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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Miyagaki T, Sugaya M. Immunological milieu in mycosis fungoides and Sézary syndrome. J Dermatol 2015; 41:11-8. [PMID: 24438139 DOI: 10.1111/1346-8138.12305] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 09/01/2013] [Indexed: 12/11/2022]
Abstract
Tumor genesis and development are driven by a combination of intrinsic events such as oncogene activation and tumor-suppressor gene inactivation, and extrinsic events that are dependent on the interaction with the stroma. Different types of growth factors, cytokines and chemokines secreted by the surrounding stromal cells are thought to play key roles in solid tumor progression. Accumulating evidence indicates that the immunological milieu plays an essential role in tumor development, not only in solid tumors, but also in hematopoietic malignancies. Understanding the interactions between tumor cells and microenvironment in mycosis fungoides (MF) and Sézary syndrome (SS) could provide a basis for the development of new treatments for these diseases that are sometimes resistant to current therapies. This article focuses on the wide variety of cell types and immunological milieus, affecting the characteristic features of MF and SS, such as skin-homing of tumor cells, T-helper type 2-dominant tumor microenvironment, accumulation of dermal dendritic cells, epidermal hyperplasia, angiogenesis and pruritus.
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Affiliation(s)
- Tomomitsu Miyagaki
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
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40
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Miyagaki T, Sugaya M, Oka T, Fujita H, Sato S. Serum chemokine levels differentially regulated by vorinostat in a Sézary syndrome patient. Br J Dermatol 2015; 173:620-2. [PMID: 25640919 DOI: 10.1111/bjd.13696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- T Miyagaki
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - M Sugaya
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - T Oka
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - H Fujita
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - S Sato
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Herías V, Biessen EAL, Beckers C, Delsing D, Liao M, Daemen MJ, Pham CCTN, Heeneman S. Leukocyte cathepsin C deficiency attenuates atherosclerotic lesion progression by selective tuning of innate and adaptive immune responses. Arterioscler Thromb Vasc Biol 2014; 35:79-86. [PMID: 25395616 DOI: 10.1161/atvbaha.114.304292] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE The protein degrading activity of cathepsin C (CatC), combined with its role in leukocyte granule activation, suggests a contribution of this cystein protease in atherosclerosis. However, no experimental data are available to validate this concept. APPROACH AND RESULTS CatC gene and protein expression were increased in ruptured versus advanced stable human carotid artery lesions. To assess causal involvement of CatC in plaque progression and stability, we generated LDLr(-/-)//CatC(-/-) chimeras by bone marrow transplantation. CatC(-/-) chimeras presented attenuated plaque burden in carotids, descending aorta, aortic arch and root, at both the early and advanced plaque stage. CatC was abundantly expressed by plaque macrophages and foam cells. CatC expression and activity were dramatically downregulated in plaques of CatC(-/-) chimeras, supporting a hematopoietic origin of plaque CatC. Our studies unveiled an unexpected feedback of CatC deficiency on macrophage activation programs and T helper cell differentiation in as much as that CatC expression was upregulated in M1 macrophages, whereas its deficiency led to combined M2 (in vitro) and Th2 polarization (in vivo). CONCLUSIONS Our data implicate CatC has a role in the selective tuning of innate and adaptive immune responses, relevant to a chronic immune disease, such as atherosclerosis.
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Affiliation(s)
- Veronica Herías
- From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.)
| | - Erik A L Biessen
- From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.)
| | - Cora Beckers
- From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.)
| | - Dianne Delsing
- From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.)
| | - Mengyang Liao
- From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.)
| | - Mat J Daemen
- From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.)
| | - Christine C T N Pham
- From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.)
| | - Sylvia Heeneman
- From the Experimental Vascular Pathology and Cardiovascular Research Institute Maastricht (CARIM), Department of Pathology, Maastricht University, The Netherlands (V.H., E.A.L.B., C.B., S.H.); Department of Immune Therapeutics, Merck Sharp & Dohme, Oss, The Netherlands (D.D.); Department of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (M.L.); Department of Pathology M2-206, Academic Medical Centre, Amsterdam, The Netherlands (M.J.D.); and Department of Medicine and Pathology and Immunology, Washington University, St Louis, MO (C.T.N.P.).
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42
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Sugaya M. Chemokines and Skin Diseases. Arch Immunol Ther Exp (Warsz) 2014; 63:109-15. [DOI: 10.1007/s00005-014-0313-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 08/26/2014] [Indexed: 10/24/2022]
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Geskin LJ, Akilov OE, Lin Y, Lokshin AE. Distinct age-matched serum biomarker profiles in patients with cutaneous T-cell lymphoma. Exp Dermatol 2014; 23:598-600. [PMID: 24862743 DOI: 10.1111/exd.12455] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2014] [Indexed: 11/28/2022]
Abstract
Immunological functions decline with age. Because MS/SzS predominately affects the elderly, it is important to distinguish age-related from cancer-specific changes. Also, MF and SzS are malignancies of CD4(+) T-lymphocytes, further compromising an immune state of the patients. The objectives of this study were to distinguish disease-specific immunological deterioration by performing comparative age-matched Luminex multiplex assessment of 34 serum biomarkers between patients with MF/SzS, HIV-infected individuals and normal controls. Controlling for age, expression level appears to significantly differ between patients with MF/SzS and controls for the following biomarkers: G-CSF, IL-5, MIP-1β, TNF-α, VEGF, EOTAXIN, IL-8, IL-12, IL-2R, IP10, MCP-1, MIG, TNFR1 and TNFR2 (P < 0.05), while others showed normal age-related changes. Interestingly, cluster analysis placed MF/SzS profiles closer to HIV. This further underscores an immunologically compromised state of patients with MF/SzS and suggests its potential self-perpetuating role in disease progression.
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Affiliation(s)
- Larisa J Geskin
- Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Dermatology, Columbia University, New York, NY, USA
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Zhou J, Xiang Y, Yoshimura T, Chen K, Gong W, Huang J, Zhou Y, Yao X, Bian X, Wang JM. The role of chemoattractant receptors in shaping the tumor microenvironment. BIOMED RESEARCH INTERNATIONAL 2014; 2014:751392. [PMID: 25110692 PMCID: PMC4119707 DOI: 10.1155/2014/751392] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 06/17/2014] [Indexed: 12/13/2022]
Abstract
Chemoattractant receptors are a family of seven transmembrane G protein coupled receptors (GPCRs) initially found to mediate the chemotaxis and activation of immune cells. During the past decades, the functions of these GPCRs have been discovered to not only regulate leukocyte trafficking and promote immune responses, but also play important roles in homeostasis, development, angiogenesis, and tumor progression. Accumulating evidence indicates that chemoattractant GPCRs and their ligands promote the progression of malignant tumors based on their capacity to orchestrate the infiltration of the tumor microenvironment by immune cells, endothelial cells, fibroblasts, and mesenchymal cells. This facilitates the interaction of tumor cells with host cells, tumor cells with tumor cells, and host cells with host cells to provide a basis for the expansion of established tumors and development of distant metastasis. In addition, many malignant tumors of the nonhematopoietic origin express multiple chemoattractant GPCRs that increase the invasiveness and metastasis of tumor cells. Therefore, GPCRs and their ligands constitute targets for the development of novel antitumor therapeutics.
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Affiliation(s)
- Jiamin Zhou
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Endoscopic Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yi Xiang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
- Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Teizo Yoshimura
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Keqiang Chen
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
| | - Wanghua Gong
- Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA
| | - Jian Huang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ye Zhou
- Department of Gastric Cancer and Soft Tissue Surgery, Fudan University Cancer Center, Shanghai 200032, China
| | - Xiaohong Yao
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Xiuwu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ji Ming Wang
- Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
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45
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Suga H, Sugaya M, Miyagaki T, Ohmatsu H, Kawaguchi M, Takahashi N, Fujita H, Asano Y, Tada Y, Kadono T, Sato S. Skin barrier dysfunction and low antimicrobial peptide expression in cutaneous T-cell lymphoma. Clin Cancer Res 2014; 20:4339-48. [PMID: 24919568 DOI: 10.1158/1078-0432.ccr-14-0077] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Atopic dermatitis is characterized by decreased expression of filaggrin and loricrin. Patients with atopic dermatitis often suffer from skin infections, which are also frequently seen in patients with cutaneous T-cell lymphoma (CTCL). In this study, we aimed to investigate the skin barrier in CTCL. EXPERIMENTAL DESIGN We assessed skin moisture and transepidermal water loss (TEWL) in patients with CTCL. We next examined mRNA expression levels of filaggrin, loricrin, and antimicrobial peptides (AMP) in skin samples of CTCL, using skin from healthy volunteers and patients with atopic dermatitis or psoriasis as controls. Immunostainings for filaggrin, loricrin, and S100 proteins were also performed. RESULTS Lower levels of skin moisture accompanied by higher levels of TEWL were seen in lesional skin of CTCL than in normal skin. CTCL lesional skin contained lower levels of filaggrin and loricrin mRNA than normal skin, which was also true with atopic dermatitis and psoriatic skin. mRNA expression levels of filaggrin in CTCL skin negatively correlated with disease severity markers. Expression levels of AMPs in lesional skin of CTCL and atopic dermatitis were significantly lower than in psoriatic skin. Immunohistochemistry confirmed decreased expression of filaggrin and loricrin in CTCL, atopic dermatitis, and psoriatic skin and enhanced expression of S100 proteins in psoriatic skin. CONCLUSIONS Our results show that there is barrier dysfunction in CTCL skin, similar to what is seen with atopic dermatitis skin. In addition, low AMP expression in CTCL skin was documented when compared with psoriatic skin, which may explain frequent infections that can occur in patients with CTCL.
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Affiliation(s)
- Hiraku Suga
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Makoto Sugaya
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Tomomitsu Miyagaki
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Hanako Ohmatsu
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Makiko Kawaguchi
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Naomi Takahashi
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Hideki Fujita
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Yoshihide Asano
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Yayoi Tada
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Takafumi Kadono
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
| | - Shinichi Sato
- Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
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46
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The Role of IL-32 in Cutaneous T-Cell Lymphoma. J Invest Dermatol 2014; 134:1428-1435. [DOI: 10.1038/jid.2013.488] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 09/30/2013] [Accepted: 10/25/2013] [Indexed: 12/20/2022]
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47
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Adar T, Shteingart S, Ben Ya'acov A, Bar-Gil Shitrit A, Goldin E. From airway inflammation to inflammatory bowel disease: eotaxin-1, a key regulator of intestinal inflammation. Clin Immunol 2014; 153:199-208. [PMID: 24786916 DOI: 10.1016/j.clim.2014.04.012] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 04/17/2014] [Accepted: 04/22/2014] [Indexed: 02/06/2023]
Abstract
Eotaxin-1 (CCL-11) is a potent eosinophil chemoattractant that is considered a major contributor to tissue eosinophilia. Elevated eotaxin-1 levels have been described in various pathologic conditions, ranging from airway inflammation, to Hodgkin lymphoma, obesity and coronary artery disease. The main receptor for eotaxin-1 is CCR3; however, recent evidence indicates that eotaxin-1 may also bind to other receptors expressed by various cell types, suggesting a more widespread regulatory role for eotaxin-1 beyond the recruitment of eosinophils. Eotaxin-1 is also strongly associated with various gastrointestinal (GI) disorders. Although the etiology of inflammatory bowel disease (IBD) is still unknown, eotaxin-1 may play a key role in the development of mucosal inflammation. In this review, we summarize the biological context and effects of eotaxin-1, as well as its potential role as a therapeutic target, with a special focus on gastrointestinal inflammation.
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Affiliation(s)
- Tomer Adar
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel.
| | - Shimon Shteingart
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Ami Ben Ya'acov
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Ariella Bar-Gil Shitrit
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - Eran Goldin
- Digestive Disease Institute, Shaare Zedek Medical Center, affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
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48
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Sugaya M, Tokura Y, Hamada T, Tsuboi R, Moroi Y, Nakahara T, Amano M, Ishida S, Watanabe D, Tani M, Ihn H, Aoi J, Iwatsuki K. Phase II study of i.v. interferon-gamma in Japanese patients with mycosis fungoides. J Dermatol 2013; 41:50-6. [DOI: 10.1111/1346-8138.12341] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Accepted: 10/13/2013] [Indexed: 01/16/2023]
Affiliation(s)
- Makoto Sugaya
- Department of Dermatology; Faculty of Medicine; University of Tokyo; Tokyo Japan
| | - Yoshiki Tokura
- Department of Dermatology; Hamamatsu University School of Medicine; Shizuoka Japan
| | - Toshihisa Hamada
- Departments of Dermatology; Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences; Okayama Japan
| | - Ryoji Tsuboi
- Department of Dermatology; Tokyo Medical University; Tokyo Japan
| | - Yoichi Moroi
- Department of Dermatology; Graduate School of Medical Sciences; Kyushu University; Fukuoka Japan
| | - Takeshi Nakahara
- Department of Dermatology; Graduate School of Medical Sciences; Kyushu University; Fukuoka Japan
| | - Masahiro Amano
- Department of Dermatology; Faculty of Medicine; University of Miyazaki; Miyazaki Japan
| | - Syuichi Ishida
- Department of Dermatology; Yokohama City University School of Medicine; Kanagawa Japan
| | - Daisuke Watanabe
- Department of Dermatology; Aichi Medical University; Nagoya Japan
| | - Mamori Tani
- Department of Dermatology; Osaka University Graduate School of Medicine; Osaka Japan
| | - Hironobu Ihn
- Department of Dermatology and Plastic Surgery; Kumamoto University; Kumamoto Japan
| | - Jun Aoi
- Department of Dermatology and Plastic Surgery; Kumamoto University; Kumamoto Japan
| | - Keiji Iwatsuki
- Departments of Dermatology; Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences; Okayama Japan
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The microenvironment in T-cell lymphomas: emerging themes. Semin Cancer Biol 2013; 24:49-60. [PMID: 24316493 DOI: 10.1016/j.semcancer.2013.11.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 11/26/2013] [Accepted: 11/29/2013] [Indexed: 11/20/2022]
Abstract
Peripheral T-cell lymphomas (PTCLs) are heterogeneous and uncommon malignancies characterized by an aggressive clinical course and a mostly poor outcome with current treatment strategies. Despite novel insights into their pathobiology provided by recent genome-wide molecular studies, several entities remain poorly characterized. In addition to the neoplastic cell population, PTCLs have a microenvironment component, composed of non-tumor cells and stroma, which is quantitatively and qualitatively variable, and which may have an effect on their pathological and clinical features. The best example is provided by angioimmunoblastic T-cell lymphoma (AITL), a designation reflecting the typical vascularization and reactive immunoblastic content of the tumor tissues. In this disease, a complex network of interactions between the lymphoma cells and the microenvironment exists, presumably mediated by the neoplastic T cells with follicular helper T-cell properties. A better understanding of the crosstalk between neoplastic T or NK cells and their microenvironment may have important implications for guiding the development of novel therapies.
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Abstract
Inappropriately regulated expression of interleukin (IL)-17A is associated with the development of inflammatory diseases and cancer. However, little is known about the role of other IL-17 family members in carcinogenesis. Here, we show that a set of malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL) spontaneously secrete IL-17F and that inhibitors of Janus kinases and Signal transducer and activator of transcription 3 are able to block that secretion. Other malignant T-cell lines produce IL-17A but not IL-17F. Upon activation, however, some of the malignant T-cell lines are able to coexpress IL-17A and IL-17F, leading to formation of IL-17A/F heterodimers. Clinically, we demonstrate that IL-17F messenger RNA expression is significantly increased in CTCL skin lesions compared with healthy donors and patients with chronic dermatitis. IL-17A expression is also increased and a significant number of patients express high levels of both IL-17A and IL-17F. Concomitantly, we observed that the expression of the IL-17 receptor is significantly increased in CTCL skin lesions compared with control subjects. Importantly, analysis of a historic cohort of 60 CTCL patients indicates that IL-17F expression is associated with progressive disease. These findings implicate IL-17F in the pathogenesis of CTCL and suggest that IL-17 cytokines and their receptors may serve as therapeutic targets.
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