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Vadivel CK, Willerslev-Olsen A, Namini MRJ, Zeng Z, Yan L, Danielsen M, Gluud M, Pallesen EMH, Wojewoda K, Osmancevic A, Hedebo S, Chang YT, Lindahl LM, Koralov SB, Geskin LJ, Bates SE, Iversen L, Litman T, Bech R, Wobser M, Guenova E, Kamstrup MR, Ødum N, Buus TB. Staphylococcus aureus induces drug resistance in cancer T cells in Sézary syndrome. Blood 2024; 143:1496-1512. [PMID: 38170178 PMCID: PMC11033614 DOI: 10.1182/blood.2023021671] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 11/16/2023] [Accepted: 12/17/2023] [Indexed: 01/05/2024] Open
Abstract
ABSTRACT Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus-specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus.
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Affiliation(s)
- Chella Krishna Vadivel
- 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
| | - Martin R. J. Namini
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Ziao Zeng
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Lang Yan
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Maria Danielsen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Maria Gluud
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Emil M. H. Pallesen
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Karolina Wojewoda
- Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Amra Osmancevic
- Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Signe Hedebo
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Yun-Tsan Chang
- Department of Dermatology and Venereology, University Hospital Centre (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Lise M. Lindahl
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Sergei B. Koralov
- Department of Pathology, New York University School of Medicine, New York, NY
| | - Larisa J. Geskin
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY
| | - Susan E. Bates
- Division of Hematology/Oncology, Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY
| | - Lars Iversen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Thomas Litman
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Rikke Bech
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Marion Wobser
- Department of Dermatology, University Hospital Würzburg, Würzburg, Germany
| | - Emmanuella Guenova
- Department of Dermatology and Venereology, University Hospital Centre (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
| | - Maria R. Kamstrup
- Department of Dermatology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Niels Ødum
- 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
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Cao M, Lai P, Liu X, Liu F, Qin Y, Tu P, Wang Y. ATF5 promotes malignant T cell survival through the PI3K/AKT/mTOR pathway in cutaneous T cell lymphoma. Front Immunol 2023; 14:1282996. [PMID: 38223508 PMCID: PMC10786347 DOI: 10.3389/fimmu.2023.1282996] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/08/2023] [Indexed: 01/16/2024] Open
Abstract
Backgrounds Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma characterized by skin infiltration of malignant T cells. The biological overlap between malignant T cells and their normal counterparts has brought obstacles in identifying tumor-specific features and mechanisms, limiting current knowledge of CTCL pathogenesis. Transcriptional dysregulation leading to abnormal gene expression profiles contributes to the initiation, progression and drug resistance of cancer. Therefore, we aimed to identify tumor-specific transcription factor underlying CTCL pathology. Methods We analyzed and validated the differentially expressed genes (DEGs) in malignant T cells based on single-cell sequencing data. Clinical relevance was evaluated based on progression-free survival and time to next treatment. To determine the functional importance, lentivirus-mediated gene knockdown was conducted in two CTCL cell lines Myla and H9. Cell survival was assessed by examining cell viability, colony-forming ability, in-vivo tumor growth in xenograft models, apoptosis rate and cell-cycle distribution. RNA sequencing was employed to investigate the underlying mechanisms. Results Activating transcription factor 5 (ATF5) was overexpressed in malignant T cells and positively correlated with poor treatment responses in CTCL patients. Mechanistically, ATF5 promoted the survival of malignant T cells partially through the PI3K/AKT/mTOR pathway, and imparted resistance to endoplasmic reticulum (ER) stress-induced apoptosis. Conclusions These findings revealed the tumor-specific overexpression of the transcription factor ATF5 with its underlying mechanisms in promoting tumor survival in CTCL, providing new insight into the understanding of CTCL's pathology.
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Affiliation(s)
- Mengzhou Cao
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Pan Lai
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Xiangjun Liu
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Fengjie Liu
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Yao Qin
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Ping Tu
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Yang Wang
- Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China
- Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China
- National Clinical Research Center for Skin and Immune Diseases, Beijing, China
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Velatooru LR, Hu CH, Bijani P, Wang X, Bojaxhi P, Chen H, Duvic M, Ni X. New JAK3-INSL3 Fusion Transcript-An Oncogenic Event in Cutaneous T-Cell Lymphoma. Cells 2023; 12:2381. [PMID: 37830594 PMCID: PMC10572011 DOI: 10.3390/cells12192381] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/14/2023] Open
Abstract
Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays were conducted in two CTCL cell lines (MJ cells and HH cells) by RNA interference and/or CRISPR/Cas9 gene editing. SS patients expressed heterogeneous levels of a new JAK3-INSL3 fusion transcript. Patients with high-level expression of JAK3-INSL3 showed poorer 5-year survival (n = 19, 42.1%) than patients with low-level expression (n = 14, 78.6%). CTCL cells transduced with specific shRNAs or sgRNAs had decreased new JAK3-INSL3 fusion transcript expression, reduced cell proliferation, and decreased colony formation. In NSG xenograft mice, smaller tumor sizes were observed in MJ cells transduced with specific shRNAs than cells transduced with controls. Our results suggest that the newly identified JAK3-INSL3 fusion transcript confers an oncogenic event in CTCL.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiao Ni
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (L.R.V.); (C.H.H.); (P.B.); (X.W.); (P.B.); (H.C.); (M.D.)
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Lee H. Mycosis fungoides and Sézary syndrome. Blood Res 2023; 58:66-82. [PMID: 37105561 PMCID: PMC10133849 DOI: 10.5045/br.2023.2023023] [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: 01/26/2023] [Revised: 04/16/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) are a distinct disease entity of cutaneous T-cell lymphoma with heterogenous clinical features and prognosis. MF mainly involves skin and usually shows an indolent and favorable clinical course. In patients with advanced-stage disease, extracutaneous involvement including lymph nodes, viscera, and blood, or large cell transformation may be observed. SS is a leukemic form of advanced-stage MF, characterized by generalized erythroderma. Early-stage MF can be treated with skin-directed therapy. However, patients with refractory or advanced-stage disease are associated with severe symptoms or poor prognosis, requiring systemic therapy. Recent progress in understanding the pathogenesis of MF/SS has contributed to advances in the management of these rare diseases. This review aims to describe the clinical manifestations, diagnosis, risk stratification, and treatment strategy of MF/SS, focusing on the recent updates in the management of these diseases.
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Affiliation(s)
- Hyewon Lee
- Division of Hemato-Oncology, Department of Internal Medicine, and Center for Hematologic Malignancy, Research Institute and Hospital, National Cancer Center, Goyang, Korea
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Peiffer L, Gambichler T, Buus TB, Horny K, Gravemeyer J, Furtmann F, Spassova I, Kubat L, Susok L, Stranzenbach R, Srinivas N, Ødum N, Becker JC. Phenotypic plasticity of malignant T cells in blood and skin of a Sézary syndrome patient revealed by single cell transcriptomics. Front Oncol 2023; 13:1090592. [PMID: 36761972 PMCID: PMC9905421 DOI: 10.3389/fonc.2023.1090592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 01/03/2023] [Indexed: 01/26/2023] Open
Abstract
Background Sézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma. Objective To compare the transcriptome of single cells in blood and skin samples from a patient with advanced SS. Methods We utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA-seq). Results We scrutinized the malignant T cells in blood and skin in an unbiased manner without pre-sorting of cells. We observed different phenotypes of the same monoclonal malignant T-cell population, confirmed by TCR sequencing and inferred copy number variation analysis. Malignant T cells present in the circulating blood expressed genes resembling central memory T cells such as CCR7, IL7R and CD27. In the skin, we detected two major malignant T-cell populations: One subpopulation was closely related to the malignant T cells from the blood, while the other subpopulation expressed genes reminiscent of skin resident effector memory T cells including GZMB and NKG7. Pseudotime analysis indicated crucial transcriptomic changes in the transition of malignant T cells between blood and skin. These changes included the differential regulation of TXNIP, a putative tumor suppressor in CTCL, and the adaptation to the hypoxic conditions in the skin. Tumor cell proliferation in the skin was supported by stimulating interactions between myeloid cells and malignant T cells. Conclusions Using scRNA-seq we detected a high degree of functional heterogeneity within the malignant T-cell population in SS and highlighted crucial differences between SS cells in blood and skin.
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Affiliation(s)
- Lukas Peiffer
- Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany,Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany,Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Thilo Gambichler
- Skin Cancer Center, Department of Dermatology, Venereology, and Allergology, Ruhr-University, Bochum, Germany,*Correspondence: Thilo Gambichler,
| | - Terkild B. Buus
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Kai Horny
- Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany,Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Jan Gravemeyer
- Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany,Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Frauke Furtmann
- Department of Dermatology, University of Essen, Essen, Germany
| | - Ivelina Spassova
- Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany,Department of Dermatology, University of Essen, Essen, Germany
| | - Linda Kubat
- Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany,Department of Dermatology, University of Essen, Essen, Germany
| | - Laura Susok
- Skin Cancer Center, Department of Dermatology, Venereology, and Allergology, Ruhr-University, Bochum, Germany
| | - René Stranzenbach
- Skin Cancer Center, Department of Dermatology, Venereology, and Allergology, Ruhr-University, Bochum, Germany
| | - Nalini Srinivas
- Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany,Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Niels Ødum
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Jürgen C. Becker
- Translational Skin Cancer Research, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Germany,Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany,Department of Dermatology, University of Essen, Essen, Germany
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Hristov AC, Tejasvi T, Wilcox RA. Cutaneous T-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol 2023; 98:193-209. [PMID: 36226409 PMCID: PMC9772153 DOI: 10.1002/ajh.26760] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 10/05/2022] [Indexed: 02/04/2023]
Abstract
DISEASE OVERVIEW Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or the blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
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Affiliation(s)
- Alexandra C. Hristov
- Departments of Pathology and Dermatology, 2800 Plymouth Road, Building 35, Ann Arbor, MI 48109-2800
| | - Trilokraj Tejasvi
- Department of Dermatology, 1910 Taubman Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109
| | - Ryan A. Wilcox
- Correspondence to: Ryan Wilcox, MD, PhD, Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Rogel Cancer Center, 1500 E. Medical Center Drive, Room 4310 CC, Ann Arbor, MI 48109-5948, Phone: (734) 615-9799, Fax: (734) 936-7376,
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To V, Evtimov VJ, Jenkin G, Pupovac A, Trounson AO, Boyd RL. CAR-T cell development for Cutaneous T cell Lymphoma: current limitations and potential treatment strategies. Front Immunol 2022; 13:968395. [PMID: 36059451 PMCID: PMC9433932 DOI: 10.3389/fimmu.2022.968395] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/27/2022] [Indexed: 11/21/2022] Open
Abstract
Chimeric antigen receptor (CAR)-T therapy has demonstrated remarkable outcomes for B cell malignancies, however, its application for T cell lymphoma, particularly cutaneous T cell lymphoma (CTCL), has been limited. Barriers to effective CAR-T cell therapy in treating CTCL include T cell aplasia in autologous transplants, CAR-T product contamination with leukemic T cells, CAR-T fratricide (when the target antigen is present on normal T cells), and tumor heterogeneity. To address these critical challenges, innovative CAR engineering by targeting multiple antigens to strike a balance between efficacy and safety of the therapy is necessary. In this review, we discuss the current obstacles to CAR-T cell therapy and highlight potential targets in treating CTCL. Looking forward, we propose strategies to develop more powerful dual CARs that are advancing towards the clinic in CTCL therapy.
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Affiliation(s)
- Van To
- Cartherics Pty Ltd, Notting Hill, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
| | | | - Graham Jenkin
- Cartherics Pty Ltd, Notting Hill, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | | | - Alan O. Trounson
- Cartherics Pty Ltd, Notting Hill, VIC, Australia
- Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC, Australia
- Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
| | - Richard L. Boyd
- Cartherics Pty Ltd, Notting Hill, VIC, Australia
- *Correspondence: Richard L. Boyd,
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Kroft SH, Harrington AM. How I Diagnose Mature T-Cell Proliferations by Flow Cytometry. Am J Clin Pathol 2022; 158:456-471. [PMID: 35929508 DOI: 10.1093/ajcp/aqac079] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 05/17/2022] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Mature T-cell neoplasms are a challenging area of diagnostic hematopathology. Flow cytometry has emerged as a useful technique for T-cell assessment. METHODS We discuss the application of flow cytometry to the evaluation of mature T-cell proliferations, to include illustrative cases, theoretical framework, detailed review of normal and reactive T-cell subsets, and examination of diagnostic pitfalls. RESULTS Immunophenotypic aberrancy can be construed as a direct expression of the neoplastic phenotype, in contrast to clonal expansion, which is seen in reactive and neoplastic T-cell proliferations. Major and minor T-cell subsets show characteristic patterns of antigen expression. Reactive states can manifest expansions of normal minor subsets and also show alterations of antigen expression on certain populations. However, some patterns of antigen expression are either never or very rarely encountered in reactive T cells. Flow cytometric tools are now available to directly assess clonality in specific T-cell populations. Technical and biological pitfalls may complicate the interpretation of T-cell flow cytometry. CONCLUSIONS Flow cytometry is a very useful tool in the diagnostic armamentarium for the assessment of mature T-cell proliferations, but it must be interpreted based on a thorough knowledge of the T-cell immune response, as well as an awareness of clinical context.
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Lewis NE, Gao Q, Petrova-Drus K, Pulitzer M, Sigler A, Baik J, Moskowitz AJ, Horwitz SM, Dogan A, Roshal M. PD-1 improves accurate detection of Sezary cells by flow cytometry in peripheral blood in mycosis fungoides/Sezary syndrome. CYTOMETRY. PART B, CLINICAL CYTOMETRY 2022; 102:189-198. [PMID: 35451196 PMCID: PMC9162159 DOI: 10.1002/cyto.b.22070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/27/2022] [Accepted: 04/07/2022] [Indexed: 05/03/2023]
Abstract
BACKGROUND Accurate Sezary cell detection in peripheral blood of mycosis fungoides/Sezary syndrome (MF/SS) patients by flow cytometry can be difficult due to overlapping immunophenotypes with normal T cells using standard markers. We assessed the utility of programmed death-1 (PD-1/CD279), a transmembrane protein expressed in some hematopoietic cells, for identification and quantitation of circulating Sezary cells among established markers using flow cytometry. METHODS 50 MF/SS and 20 control blood samples were immunophenotyped by flow cytometry. Principal component analysis (PCA) assessed contributions of antigens to separation of abnormal from normal T cell populations. PD-1 was assessed over time in blood and bone marrow of available MF/SS cases. RESULTS Normal CD4+ T cells showed dim/intermediate to absent PD-1 expression. PD-1 in Sezary cells was informatively brighter (≥1/3 log) than internal normal CD4+ T cells in 39/50 (78%) cases. By PCA, PD-1 ranked 3rd behind CD7 and CD26 in population separation as a whole; it ranked in the top 3 markers in 32/50 (64%) cases and 1st in 4/50 (8%) cases when individual abnormal populations were compared to total normal CD4+ T cells. PD-1 clearly separated Sezary from normal CD4+ T cells in 15/26 (58%, 30% of total) cases with few and subtle alterations of pan-T cell antigens/CD26 and was critical in 6 (12% of total), without which identification and quantification were significantly affected or nearly impossible. PD-1 remained informative in blood/bone marrow over time in most patients. CONCLUSIONS PD-1 significantly contributes to accurate flow cytometric Sezary cell assessment in a routine Sezary panel.
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Affiliation(s)
- Natasha E Lewis
- Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Qi Gao
- Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kseniya Petrova-Drus
- Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Diagnostic Molecular Pathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Melissa Pulitzer
- Dermatopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Allison Sigler
- Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jeeyeon Baik
- Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alison J Moskowitz
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Steven M Horwitz
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ahmet Dogan
- Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mikhail Roshal
- Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Ni X, Maiti S, Redko A, Bijani P, Duvic M. Monitoring malignant T-cell clones by direct TCR expression assay in patients with leukemic cutaneous T-cell lymphoma during extracorporeal photopheresis. PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE 2022; 38:158-168. [PMID: 34543492 PMCID: PMC11917527 DOI: 10.1111/phpp.12732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/08/2021] [Accepted: 09/15/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND/PURPOSE Accurate assessment of malignant T-cell clones in patients with leukemic cutaneous T-cell lymphoma (L-CTCL) is crucial for diagnosis, treatment, and monitoring disease. Although multiple approaches to quantitate malignant T-cell clones have been reported, a cost-effective assay with broad coverage is not available. We report a NanoString-nCounter-Technology-based direct TCR expression assay (DTEA) that was previously developed to quantify both TCR-Vα and TCR-Vβ usages after adoptive immunotherapy. This study was performed to test the effectiveness of DTEA in assessing malignant T-cell clones in L-CTCL patients. METHODS Total RNAs extracted from peripheral blood mononuclear cells of patients before starting extracorporeal photopheresis (ECP) (n = 15) and during therapy at 3 months and 6 months (n = 12) were used for DTEA, with customized probes for 45 TCR-Vα and 46 TCR-Vβ family members. RESULTS At baseline, DTEA detected TCR-Vβ clones in all 15 patients (100%) compared to flow cytometry that detected TCR-Vβ clones in 9 of 13 patients (69.2%). In addition to predominant TCR-Vβ clones, DTEA also detected additional TCR-Vβ clones in 8 of 15 patients (53.3%). Furthermore, DTEA simultaneously identified clonal TCR-Vα usages, which allowed us to pair TCR-Vα and TCRVβ usages by malignant T-cells and identify diversified clonotypes. Changes in the relative frequencies of clonal TCR-Vβ and TCRVα usages over therapy were consistent with patients' clinical responses. CONCLUSIONS Our results indicate that DTEA can effectively assess malignant T-cell clones by detecting clonal TCR-Vα and TCR-Vβ usages. By providing a global view of TCR repertoires, DTEA may also help us understand the origin(s) of malignant T-cells and pathogenesis of CTCL.
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Affiliation(s)
- Xiao Ni
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sourindra Maiti
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alissa Redko
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pedram Bijani
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Madeleine Duvic
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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11
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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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12
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The Serine Protease CD26/DPP4 in Non-Transformed and Malignant T Cells. Cancers (Basel) 2021; 13:cancers13235947. [PMID: 34885056 PMCID: PMC8657226 DOI: 10.3390/cancers13235947] [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: 11/15/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The transmembrane serine protease CD26/Dipeptidylpeptidase 4 modulates T-cell activation, proliferation, and effector function. Due to their remarkable tumoricidal properties CD26-positive T cells are considered promising candidates for T cell-based immunotherapies while in cutaneous T cell lymphoma CD26/DPP4 expression patterns are established markers for diagnosis and possibly prognosis. With a focus on T cells, we review current knowledge on the regulation of CD26/DPP4 expression and release, its implication in T-cell effector function and the suitability CD26/DPP4 as a diagnostic and/or prognostic factor in T-cell malignancies. Abstract CD26/Dipeptidylpeptidase 4 is a transmembrane serine protease that cleaves off N-terminal dipeptides. CD26/DPP4 is expressed on several immune cell types including T and NK cells, dendritic cells, and activated B cells. A catalytically active soluble form of CD26/DPP4 can be released from the plasma membrane. Given its wide array of substrates and interaction partners CD26/DPP4 has been implicated in numerous biological processes and effects can be dependent or independent of its enzymatic activity and are exerted by the transmembrane protein and/or the soluble form. CD26/DPP4 has been implicated in the modulation of T-cell activation and proliferation and CD26/DPP4-positive T cells are characterized by remarkable anti-tumor properties rendering them interesting candidates for T cell-based immunotherapies. Moreover, especially in cutaneous T-cell lymphoma CD26/DPP4 expression patterns emerged as an established marker for diagnosis and treatment monitoring. Surprisingly, besides a profound knowledge on substrates, interaction partners, and associated signal transduction pathways, the precise role of CD26/DPP4 for T cell-based immune responses is only partially understood.
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13
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Hristov AC, Tejasvi T, Wilcox RA. Cutaneous T-cell lymphomas: 2021 update on diagnosis, risk-stratification, and management. Am J Hematol 2021; 96:1313-1328. [PMID: 34297414 PMCID: PMC8486344 DOI: 10.1002/ajh.26299] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 11/08/2022]
Abstract
DISEASE OVERVIEW Cutaneous T-cell lymphomas are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies, including biologic-response modifiers, histone deacetylase inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
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Affiliation(s)
- Alexandra C. Hristov
- Departments of Pathology and Dermatology, North Campus Research Complex, Ann Arbor, Michigan, USA
| | - Trilokraj Tejasvi
- Director Cutaneous Lymphoma program, Department of Dermatology, A. Alfred Taubman Health Care Center, Ann Arbor, Michigan, USA
| | - Ryan A. Wilcox
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, USA
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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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15
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Improved Sézary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome. Blood 2021; 138:2539-2554. [PMID: 34314480 DOI: 10.1182/blood.2021012286] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/14/2021] [Indexed: 11/20/2022] Open
Abstract
Sézary syndrome (SS) is an aggressive leukemic form of Cutaneous T-cell Lymphoma with neoplastic CD4+ T cells present in skin, lymph nodes, and blood. Despite advances in therapy, prognosis remains poor with a 5-year overall survival of 30%. The immunophenotype of Sézary cells is diverse, which hampers efficient diagnosis, sensitive disease monitoring, and accurate assessment of treatment response. Comprehensive immunophenotypic profiling of Sézary cells with an in-depth analysis of maturation and functional subsets has not been performed thus far. We immunophenotypically profiled 24 SS patients employing standardized and sensitive EuroFlow-based multiparameter flow cytometry (MFC). We accurately identified and quantified Sézary cells in blood and performed an in-depth assessment of their phenotypic characteristics in comparison with their normal counterparts in the blood CD4+ T-cell compartment. We observed inter-and intra-patient heterogeneity and phenotypic changes over time. Sézary cells exhibited phenotypes corresponding with classical and non-classical T helper subsets with different maturation phenotypes. We combined MFC analyses with FACS cell sorting and performed RNA-sequencing studies on purified subsets of malignant Sézary cells and normal CD4+ T cells of the same patients. We confirmed pure mono-clonality in Sézary subsets, we compared transcriptomes of phenotypically distinct Sézary subsets and identified novel down-regulated genes, most remarkable THEMIS and LAIR1 which discriminate Sézary cells from normal residual CD4+ T cells. Together, these findings further unravel the heterogeneity of Sézary cell subpopulations within and between patients. These new data will support improved blood staging and more accurate disease monitoring.
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16
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Durgin JS, Weiner DM, Wysocka M, Rook AH. The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: Pathways and targets for immune restoration and tumor eradication. J Am Acad Dermatol 2021; 84:587-595. [PMID: 33352267 PMCID: PMC7897252 DOI: 10.1016/j.jaad.2020.12.027] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/07/2020] [Accepted: 12/09/2020] [Indexed: 11/27/2022]
Abstract
Cutaneous T cell lymphomas (CTCLs) are malignancies of skin-trafficking T cells. Patients with advanced CTCL manifest immune dysfunction that predisposes to infection and suppresses the antitumor immune response. Therapies that stimulate immunity have produced superior progression-free survival compared with conventional chemotherapy, reinforcing the importance of addressing the immune deficient state in the care of patients with CTCL. Recent research has better defined the pathogenesis of these immune deficits, explaining the mechanisms of disease progression and revealing potential therapeutic targets. The features of the malignant cell in mycosis fungoides and Sézary syndrome are now significantly better understood, including the T helper 2 cell phenotype, regulatory T cell cytokine production, immune checkpoint molecule expression, chemokine receptors, and interactions with the microenvironment. The updated model of CTCL immunopathogenesis provides understanding into clinical progression and therapeutic response.
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Affiliation(s)
- Joseph S Durgin
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David M Weiner
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Maria Wysocka
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Alain H Rook
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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Two Cases With Features of Lymphocyte Variant Hypereosinophilic Syndrome With STAT3 SH2 Domain Mutations. Am J Surg Pathol 2021; 45:193-199. [PMID: 33060403 DOI: 10.1097/pas.0000000000001604] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Lymphocyte variant hypereosinophilic syndrome (LV-HES) is a rare cause of eosinophilia that is due to eosinophilipoietic cytokine production by an immunophenotypically abnormal T-cell clone. The molecular pathogenesis of this disorder is largely unknown and only 1 case of LV-HES with a pathogenic STAT3 mutation has been described thus far. Here we report 2 cases of LV-HES with STAT3 SH2 domain mutations. These cases further support the model that activation of STAT3 signaling through STAT3 SH2 domain mutations is a recurrent event in LV-HES.
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18
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Pan K, Ohnuma K, Morimoto C, Dang NH. CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions. Cureus 2021; 13:e13495. [PMID: 33777580 PMCID: PMC7990348 DOI: 10.7759/cureus.13495] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
CD26/Dipeptidyl peptidase IV (DPPIV) is a cell surface glycoprotein with numerous roles including glucose metabolism, immunomodulation, and tumorigenesis. CD26/DPPIV is well recognized in diabetes, with DPPIV inhibitors being a class of oral hypoglycemic drugs called gliptins that are commonly used to treat type two diabetes mellitus. Recent work also indicated a potential role for CD26 in infectious diseases, including COVID-19, and immune-mediated disorders such as rheumatoid arthritis, inflammatory bowel disease, and graft-versus-host disease. In cancer, CD26/DPPIV expression has been characterized in numerous tumors such as hematologic malignancies, malignant pleural mesothelioma (MPM), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastrointestinal stromal tumor (GIST), and prostate, lung, colorectal, and ovarian (PLCO) cancer. Hence, CD26 has been frequently studied as a tumor biomarker and therapeutic target. CD26/DPPIV-targeted therapies have been evaluated in various cancers, including the use of anti-CD26 monoclonal antibodies as anticancer treatment in selected neoplasms. This review highlights our current understanding of the role of CD26 in cancer, diabetes, immune-mediated diseases, and infectious diseases. Enhanced understanding of CD26 biology and function may lead to novel therapeutic approaches in multiple human diseases.
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Affiliation(s)
- Kelsey Pan
- Internal Medicine, University of Florida, Gainesville, USA
| | - Kei Ohnuma
- Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University, Tokyo, JPN
| | - Chikao Morimoto
- Department of Therapy Development and Innovation for Immune Disorders and Cancers, Juntendo University, Tokyo, JPN
| | - Nam H Dang
- Oncology, University of Florida, Gainesville, USA
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19
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Patel PM, Jones VA, Kridin K, Amber KT. The role of Dipeptidyl Peptidase-4 in cutaneous disease. Exp Dermatol 2020; 30:304-318. [PMID: 33131073 DOI: 10.1111/exd.14228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/21/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022]
Abstract
Dipeptidyl peptidase-4 (DPP4) is a multifunctional, transmembrane glycoprotein present on the cell surface of various tissues. It is present in multiple molecular forms including cell surface and soluble. The role of DPP4 and its inhibition in cutaneous dermatoses have been a recent point of investigation. DPP4 exerts a notable influence on T-cell biology, the induction of skin-specific lymphocytes, and the homeostasis between regulatory and effector T cells. Moreover, DPP4 interacts with a broad range of molecules, including adenosine deaminase, caveolin-1, CXCR4 receptor, M6P/insulin-like growth factor II-receptor and fibroblast activation protein-α, triggering downstream effects that modulate the immune response, cell adhesion and chemokine activity. DPP4 expression on melanocytes, keratinocytes and fibroblasts further alters cell function and, thus, has crucial implications in cutaneous pathology. As a result, DPP4 plays a significant role in bullous pemphigoid, T helper type 1-like reactions, cutaneous lymphoma, melanoma, wound healing and fibrotic disorders. This review illustrates the multifactorial role of DPP4 expression, regulation, and inhibition in cutaneous diseases.
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Affiliation(s)
- Payal M Patel
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Virginia A Jones
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Khalaf Kridin
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Kyle T Amber
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
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20
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Phenotypical Markers, Molecular Mutations, and Immune Microenvironment as Targets for New Treatments in Patients with Mycosis Fungoides and/or Sézary Syndrome. J Invest Dermatol 2020; 141:484-495. [PMID: 33162051 DOI: 10.1016/j.jid.2020.07.026] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/10/2020] [Accepted: 07/14/2020] [Indexed: 12/29/2022]
Abstract
Primary cutaneous lymphomas encompass a wide spectrum of rare lymphoproliferative disorders originating in the skin, among which, mycosis fungoides (MF) is the most common subtype. The treatment of this disease is based on skin-directed therapies eventually in association with biologic response modifiers in the early phases, whereas in patients with the advanced stages, several therapeutic strategies can be used including mono and/or polychemotherapy and bone marrow transplantation. In recent years, the identification of specific markers (phenotypical, immunological, and molecular) has led to the development of several studies (including two randomized phase III trials). The results of these studies are modifying our therapeutic strategy toward a personalized treatment approach in which the clinical characteristics of the patients and tumor-node-metastasis-blood stage are considered together with the expression of specific markers (i.e., a CD30-positive expression for the use of brentuximab vedotin). This review will provide a comprehensive scenario of the main phenotypical, molecular, and immunological markers related to MF pathogenesis and disease evolution, which could represent the target for the development of innovative effective treatments in this disease.
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21
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Lyapichev KA, Bah I, Huen A, Duvic M, Routbort MJ, Wang W, Jorgensen JL, Medeiros LJ, Vega F, Craig FE, Wang SA. Determination of immunophenotypic aberrancies provides better assessment of peripheral blood involvement by mycosis fungoides/Sézary syndrome than quantification of CD26- or CD7- CD4+ T-cells. CYTOMETRY PART B-CLINICAL CYTOMETRY 2020; 100:183-191. [PMID: 32667737 DOI: 10.1002/cyto.b.21933] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/12/2020] [Accepted: 06/10/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Blood involvement by mycosis fungoides (MF)/Sézary syndrome (SS) influences prognosis and therapeutic decisions. MF/SS blood stage is currently determined by absolute CD4 + CD26- or CD4 + CD7-cell counts, which quantification method may overestimate MF/SS by including CD26- or CD7- normal CD4+ T-cells, or underestimate disease burden when MF/SS cells show incomplete loss of CD26 and/or CD7. Recently, through the standardization effort led by the International Clinical Cytometry Society (ICCS), recommendation was made to quantify MF/SS by enumerating immunophenotypically aberrant CD4+ T-cells, rather than CD26- or CD7- in isolation. METHODS We compared these two quantitation methods in 309 MF/SS patients who had blood samples analyzed by flow cytometry immunophenotyping (FCI) over a 1-year period. RESULTS Using the European Organization of Research and Treatment of Cancer (EORTC)/International Society for Cutaneous Lymphomas (ISCL) criteria, 221 (71.5%) patients had a blood stage corresponding to B0, 57 (18.4%) to B1, and 31 (10%) to B2. By FCI analysis, a total of 62 patients (20.0%) were found positive for MF/SS. Among EORTC B0 patients, 11/221 (5%) were positive by FCI (false negatives), and among EORTC Stage B1 patients, 35/57 (61%) were negative by FCI (false positives). Regarding patients positive for MF/SS cells by FCI, there was an overall excellent correlation (r = .999, p < .001) between the EORTC/ISCL method and FCI method; however, four (6.5%) patients would have an altered B stage between B0 and B1. CONCLUSION The MF/SS cell quantification method using immunophenotypic aberrancies, as recommended by the ICCS, allows to distinguish MF/SS cells from background benign T-cells and enables for more accurate staging, especially among patients currently being considered to have B0 and B1 stage diseases.
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Affiliation(s)
- Kirill A Lyapichev
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ismael Bah
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Auris Huen
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Madeleine Duvic
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mark J Routbort
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Wei Wang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jeffrey L Jorgensen
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - L Jeffrey Medeiros
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Francisco Vega
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Fiona E Craig
- Division of Hematopathology, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Sa A Wang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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22
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Horna P, Wang SA, Wolniak KL, Psarra K, Almeida J, Illingworth AJ, Johansson U, Craig FE, Torres R. Flow cytometric evaluation of peripheral blood for suspected Sézary syndrome or mycosis fungoides: International guidelines for assay characteristics. CYTOMETRY PART B-CLINICAL CYTOMETRY 2020; 100:142-155. [PMID: 32319723 DOI: 10.1002/cyto.b.21878] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 02/22/2020] [Accepted: 03/23/2020] [Indexed: 12/25/2022]
Abstract
A peripheral blood flow cytometric assay for Sézary syndrome (SS) or circulating mycosis fungoides (MF) cells must be able to reliably identify, characterize, and enumerate T-cells with an immunophenotype that differs from non-neoplastic T-cells. Although it is also important to distinguish SS and MF from other subtypes of T-cell neoplasm, this usually requires information in addition to the immunophenotype, such as clinical and morphologic features. This article outlines the approach recommended by an international group with experience and expertise in this area. The following key points are discussed: (a) At a minimum, a flow cytometric assay for SS and MF should include the following six antibodies: CD3, CD4, CD7, CD8, CD26, and CD45. (b) An analysis template must reliably detect abnormal T-cells, even when they lack staining for CD3 or CD45, or demonstrate a phenotype that is not characteristic of normal T-cells. (c) Gating strategies to identify abnormal T-cells should be based on the identification of subsets with distinctly homogenous immunophenotypic properties that are different from those expected for normal T-cells. (d) The blood concentration of abnormal cells, based on any immunophenotypic abnormalities indicative of MF or SS, should be calculated by either direct enumeration or a dual-platform method, and reported.
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Affiliation(s)
- Pedro Horna
- Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sa A Wang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Kristy L Wolniak
- Division of Hematopathology, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Katherina Psarra
- Department of Immunology and Histocompatibility, "Evangelismos" Hospital, Athens, Greece
| | - Julia Almeida
- Cancer Research Center (IBMCC-CSIC/USAL-IBSAL), Cytometry Service (NUCLEUS) and Department of Medicine, IBSAL and CIBERONC, University of Salamanca, Salamanca, Spain
| | | | - Ulrika Johansson
- SI-HMDS University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Fiona E Craig
- Division of Hematopathology, Mayo Clinic Arizona, Phoenix, Arizona, USA
| | - Richard Torres
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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23
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Hristov AC, Tejasvi T, Wilcox RA. Mycosis fungoides and Sézary syndrome: 2019 update on diagnosis, risk-stratification, and management. Am J Hematol 2019; 94:1027-1041. [PMID: 31313347 DOI: 10.1002/ajh.25577] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 07/09/2019] [Accepted: 07/10/2019] [Indexed: 01/04/2023]
Abstract
DISEASE OVERVIEW Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS). DIAGNOSIS The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, skin-directed therapies are preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with systemic therapies. These include biologic-response modifiers, histone deacetylase (HDAC) inhibitors, or antibody-based strategies, in an escalating fashion. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
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Affiliation(s)
- Alexandra C. Hristov
- Departments of Pathology and DermatologyUniversity of Michigan Ann Arbor Michigan
| | | | - Ryan A. Wilcox
- Division of Hematology/Oncology, Department of Internal MedicineUniversity of Michigan Rogel Cancer Center Ann Arbor Michigan
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Ying Z, Shiue L, Park K, Kollet J, Bijani P, Goswami M, Duvic M, Ni X. Blood transcriptional profiling reveals IL-1 and integrin signaling pathways associated with clinical response to extracorporeal photopheresis in patients with leukemic cutaneous T-cell lymphoma. Oncotarget 2019; 10:3183-3197. [PMID: 31139332 PMCID: PMC6516711 DOI: 10.18632/oncotarget.26900] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 04/14/2019] [Indexed: 01/07/2023] Open
Abstract
Extracorporeal photopheresis (ECP) is a frontline therapy for patients with leukemic cutaneous T-cell lymphoma (L-CTCL), but its mechanisms of action are not fully understood. This study was to explore the molecular mechanisms underlying clinical response versus non-response in patients with L-CTCL. We performed blood transcriptional profiling of ten L-CTCL patients at Day 2 and 1 month post- ECP compared to pre-ECP baseline using Agilent Whole Human Genome Microarray technology. Differentially expressed genes (DEGs) between five clinically-responsive patients and five clinically-resistant patients were cross-compared. Higher numbers of genes were modulated in responders than non-responders after ECP at both Day 2 and 1 month, with two thirds of DEGs down-regulated. The down-regulated DEGs at 1 month post-ECP were related to inflammatory, immune and/or stress responses, platelet functions, and chromatin remodeling. Upregulated DEGs were mainly related to functions of the nucleolus. Pathway analysis revealed that integrin and IL-1 signaling pathways were the top pathways affected in responders, which were minimally affected in non-responders. The top upstream transcription regulators affected were IL1B, EGR1, FAS, and TGFB1. Our results suggest that the modulation of cell adhesion and suppression of IL-1β induced inflammation may underlie the efficacy of ECP in L-CTCL.
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Affiliation(s)
- Zuolin Ying
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lisa Shiue
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Katherine Park
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jutta Kollet
- Bioinformatics, Miltenyi Biotec GmbH, Beigisch Gladbach, 51429, Germany
| | - Pedram Bijani
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Meghali Goswami
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Madeleine Duvic
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xiao Ni
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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25
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Maitre E, Le‐Page A, Comoz F, Truquet F, Damaj G, Cornet E, Verneuil L, Salaün V, Troussard X. Usefulness of Flow Cytometry for the Detection of Cutaneous Localization in Malignant Hematologic Disorders. CYTOMETRY PART B-CLINICAL CYTOMETRY 2019; 96:283-293. [DOI: 10.1002/cyto.b.21784] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 04/02/2019] [Accepted: 04/10/2019] [Indexed: 12/25/2022]
Affiliation(s)
- Elsa Maitre
- Laboratoire d'hématologie, CHU de Caen, Calvados, 14033 Caen France
| | - Anne‐Laure Le‐Page
- Laboratoire d'Anatomopathologie, CHU de Caen, Calvados, 14033 Caen France
| | - Francois Comoz
- Laboratoire d'Anatomopathologie, CHU de Caen, Calvados, 14033 Caen France
| | - Florence Truquet
- Laboratoire d'hématologie, CHU de Caen, Calvados, 14033 Caen France
| | - Gandhi Damaj
- Institut d'Hématologie Bas Normand, CHU de Caen, Calvados, 14033 Caen France
| | - Edouard Cornet
- Laboratoire d'hématologie, CHU de Caen, Calvados, 14033 Caen France
| | | | - Véronique Salaün
- Laboratoire d'hématologie, CHU de Caen, Calvados, 14033 Caen France
| | - Xavier Troussard
- Laboratoire d'hématologie, CHU de Caen, Calvados, 14033 Caen France
- Institut d'Hématologie Bas Normand, CHU de Caen, Calvados, 14033 Caen France
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Enz N, Vliegen G, De Meester I, Jungraithmayr W. CD26/DPP4 - a potential biomarker and target for cancer therapy. Pharmacol Ther 2019; 198:135-159. [PMID: 30822465 DOI: 10.1016/j.pharmthera.2019.02.015] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CD26/dipeptidyl peptidase (DPP)4 is a membrane-bound protein found in many cell types of the body, and a soluble form is present in body fluids. There is longstanding evidence that various primary tumors and also metastases express CD26/DPP4 to a variable extent. By cleaving dipeptides from peptides with a proline or alanine in the penultimate position at the N-terminus, it regulates the activity of incretin hormones, chemokines and many other peptides. Due to these effects and interactions with other molecules, a tumor promoting or suppressing role can be attributed to CD26/DPP4. In this review, we discuss the existing evidence on the expression of soluble or membrane-bound CD26/DPP4 in malignant diseases, along with the most recent findings on CD26/DPP4 as a therapeutic target in specific malignancies. The expression and possible involvement of the related DPP8 and DPP9 in cancer are also reviewed. A higher expression of CD26/DPP4 is found in a wide variety of tumor entities, however more research on CD26/DPP4 in the tumor microenvironment is needed to fully explore its use as a tumor biomarker. Circulating soluble CD26/DPP4 has also been studied as a cancer biomarker, however, the observed decrease in most cancer patients does not seem to be cancer specific. Encouraging results from experimental work and a recently reported first phase clinical trial targeting CD26/DPP4 in mesothelioma, renal and urological tumors pave the way for follow-up clinical studies, also in other tumor entities, possibly leading to the development of more effective complementary therapies against cancer.
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Affiliation(s)
- Njanja Enz
- Department of Thoracic Surgery, University Hospital Rostock, Schillingallee 35, 18057 Rostock, Germany
| | - Gwendolyn Vliegen
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Ingrid De Meester
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
| | - Wolfgang Jungraithmayr
- Department of Thoracic Surgery, University Hospital Rostock, Schillingallee 35, 18057 Rostock, Germany.
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27
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Bensussan A, Janela B, Thonnart N, Bagot M, Musette P, Ginhoux F, Marie-Cardine A. Identification of CD39 as a Marker for the Circulating Malignant T-Cell Clone of Sézary Syndrome Patients. J Invest Dermatol 2019; 139:725-728. [PMID: 30798854 DOI: 10.1016/j.jid.2018.09.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 09/25/2018] [Accepted: 09/25/2018] [Indexed: 11/25/2022]
Affiliation(s)
- Armand Bensussan
- INSERM U976, Oncodermatology, Immunology and Cutaneous stem cells, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Baptiste Janela
- Agency for Science, Technology and Research (A*STAR) and Skin Research Institute of Singapore (SRIS), Singapore
| | - Nicolas Thonnart
- INSERM U976, Oncodermatology, Immunology and Cutaneous stem cells, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Martine Bagot
- INSERM U976, Oncodermatology, Immunology and Cutaneous stem cells, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France; Saint Louis Hospital, Department of Dermatology, Paris, France
| | - Philippe Musette
- INSERM U976, Oncodermatology, Immunology and Cutaneous stem cells, Paris, France
| | - Florent Ginhoux
- Agency for Science, Technology and Research (A*STAR) and Skin Research Institute of Singapore (SRIS), Singapore
| | - Anne Marie-Cardine
- INSERM U976, Oncodermatology, Immunology and Cutaneous stem cells, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
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28
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Yuki A, Shinkuma S, Hayashi R, Fujikawa H, Kato T, Homma E, Hamade Y, Onodera O, Matsuoka M, Shimizu H, Iwata H, Abe R. CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases. J Am Acad Dermatol 2018; 79:1039-1046. [DOI: 10.1016/j.jaad.2018.06.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 05/30/2018] [Accepted: 06/06/2018] [Indexed: 12/11/2022]
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29
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Torrey H, Khodadoust M, Tran L, Baum D, Defusco A, Kim YH, Faustman DL. Targeted killing of TNFR2-expressing tumor cells and T regs by TNFR2 antagonistic antibodies in advanced Sézary syndrome. Leukemia 2018; 33:1206-1218. [PMID: 30356161 PMCID: PMC6756055 DOI: 10.1038/s41375-018-0292-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 09/10/2018] [Accepted: 09/17/2018] [Indexed: 01/08/2023]
Abstract
Sézary syndrome (SS) is a rare form of cutaneous T-cell lymphoma often refractory to treatment. SS is defined as adenopathy, erythroderma with high numbers of atypical T cells. This offers an opportunity for new interventions and perhaps antibody-based therapeutic by virtue of its high expression of the TNFR2 oncogene on the tumor cells and on T-regulatory cells (Tregs). Potent human-directed TNFR2 antagonistic antibodies have been created that preferentially target the TNFR2 oncogene and tumor-infiltrating TNFR2+ Tregs. Here we test the therapeutic potential of TNFR2 antagonists on freshly isolated lymphocytes from patients with Stage IVA SS and from healthy controls. SS patients were on a variety of end-stage multi-drug therapies. Baseline burden Treg/T effector (Teff) ratios and the responsiveness of tumor and infiltrating Tregs to TNFR2 antibody killing was studied. We show dose-escalating concentrations of a dominant TNFR2 antagonistic antibody killed TNFR2+ SS tumor cells and thus restored CD26- subpopulations of lymphocyte cell numbers to normal. The abundant TNFR2+ Tregs of SS subjects are also killed with TNFR2 antagonism. Beneficial and rapid expansion of Teff was observed. The combination of Treg inhibition and Teff expansion brought the high Treg/Teff ratio to normal. Our findings suggest a marked responsiveness of SS tumor cells and Tregs, to targeting with TNFR2 antagonistic antibodies. These results show TNFR2 antibodies are potent and efficacious in vitro.
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Affiliation(s)
- H Torrey
- Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Rm 3602, 02129, Boston, MA, USA
| | - M Khodadoust
- Stanford University School of Medicine/Cancer Institute, 94305, Palo Alto, CA, USA
| | - L Tran
- Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Rm 3602, 02129, Boston, MA, USA
| | - D Baum
- Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Rm 3602, 02129, Boston, MA, USA
| | - A Defusco
- Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Rm 3602, 02129, Boston, MA, USA
| | - Y H Kim
- Stanford University School of Medicine/Cancer Institute, 94305, Palo Alto, CA, USA
| | - D L Faustman
- Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Rm 3602, 02129, Boston, MA, USA.
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30
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Wilcox RA. Cutaneous T-cell lymphoma: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 2017; 92:1085-1102. [PMID: 28872191 DOI: 10.1002/ajh.24876] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 07/27/2017] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multi-disciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
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Affiliation(s)
- Ryan A. Wilcox
- Division of Hematology/Oncology; University of Michigan Comprehensive Cancer Center; Ann Arbor Michigan 48109-5948
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31
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Vonderheid EC, Hou JS. CD4+CD26−lymphocytes are useful to assess blood involvement and define B ratings in cutaneous T cell lymphoma. Leuk Lymphoma 2017; 59:330-339. [DOI: 10.1080/10428194.2017.1334123] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Eric C. Vonderheid
- Sydney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - J. Steve Hou
- Drexel University College of Medicine, Philadelphia, PA, USA
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32
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Usefulness of KIR3DL2 to Diagnose, Follow-Up, and Manage the Treatment of Patients with Sézary Syndrome. Clin Cancer Res 2017; 23:3619-3627. [DOI: 10.1158/1078-0432.ccr-16-3185] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 01/16/2017] [Accepted: 01/18/2017] [Indexed: 11/16/2022]
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Cedeno-Laurent F, Wysocka M, Obstfeld AE, Novoa RA, Vittorio CC, Kim EJ, Weng WK, Rook AH. Gain of CD26 expression on the malignant T-cells in relapsed erythrodermic leukemic mycosis fungoides. J Cutan Pathol 2017; 44:462-466. [PMID: 28083948 DOI: 10.1111/cup.12899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 11/17/2016] [Accepted: 01/11/2017] [Indexed: 11/29/2022]
Abstract
Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction studies and high-throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.
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Affiliation(s)
- Filiberto Cedeno-Laurent
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Maria Wysocka
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Amrom E Obstfeld
- Department of Molecular Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Roberto A Novoa
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carmela C Vittorio
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ellen J Kim
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Wen-Kai Weng
- Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Alain H Rook
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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34
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Boonk SE, Zoutman WH, Marie-Cardine A, van der Fits L, Out-Luiting JJ, Mitchell TJ, Tosi I, Morris SL, Moriarty B, Booken N, Felcht M, Quaglino P, Ponti R, Barberio E, Ram-Wolff C, Jäntti K, Ranki A, Bernengo MG, Klemke CD, Bensussan A, Michel L, Whittaker S, Bagot M, Tensen CP, Willemze R, Vermeer MH. Evaluation of Immunophenotypic and Molecular Biomarkers for Sézary Syndrome Using Standard Operating Procedures: A Multicenter Study of 59 Patients. J Invest Dermatol 2016; 136:1364-1372. [DOI: 10.1016/j.jid.2016.01.038] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 01/11/2016] [Accepted: 01/25/2016] [Indexed: 10/22/2022]
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Wilcox RA. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016; 91:151-65. [PMID: 26607183 PMCID: PMC4715621 DOI: 10.1002/ajh.24233] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 11/03/2015] [Indexed: 12/11/2022]
Abstract
DISEASE OVERVIEW Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY TNMB (tumor, node, metastasis, blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors before escalating therapy to include systemic, single-agent chemotherapy. In highly-selected patients, allogeneic stem-cell transplantation may be considered, as this may be curative in some patients.
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Affiliation(s)
- Ryan A. Wilcox
- Division of Hematology/Oncology, University of Michigan Cancer Center, 1500 E. Medical Center Drive, Room 4310 CC, Ann Arbor, MI 48109-5948
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36
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Sidiropoulos KG, Martinez-Escala ME, Yelamos O, Guitart J, Sidiropoulos M. Primary cutaneous T-cell lymphomas: a review. J Clin Pathol 2015; 68:1003-10. [DOI: 10.1136/jclinpath-2015-203133] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Primary cutaneous T-cell lymphomas (CTCLs) represent a number of extranodal lymphomas arising from a malignant population of lymphocytes in the skin, with the most common type being mycosis fungoides (MF) representing half of all primary CTCLs. Despite advances in immunohistochemistry and molecular methodology, significant diagnostic challenges remain due to phenotypic overlap of primary CTCLs with several inflammatory dermatoses, secondary lymphomas, among other conditions. Clinical features such as presentation and morphology, staging, histology, immunophenotype and molecular features must be considered in detail before a diagnosis is made in order to minimise false-positive, false-negative and indeterminate diagnoses. Herein, we review primary CTCLs, including epidemiological data, a brief summary of clinical presentations, immunophenotype, molecular signatures and differential diagnoses.
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Horna P, Kurant D, Sokol L, Sotomayor EM, Moscinski L, Glass LF. Flow cytometric identification of immunophenotypically aberrant T-cell clusters on skin shave biopsy specimens from patients with mycosis fungoides. Am J Clin Pathol 2015; 143:785-96. [PMID: 25972320 DOI: 10.1309/ajcpwe2hbfcgdids] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES To assess the ability of flow cytometry (FC) to detect putative neoplastic T-cell subsets on skin shave biopsy (SSB) specimens from patients with mycosis fungoides (MF) and to study the immunophenotype of skin-infiltrating tumor cells in MF. METHODS SSB specimens from patients with suspected MF were bisected and submitted for both FC and routine histopathology. Six-dimensional gating strategies were applied to identify putative neoplastic cells, independently from their expected immunophenotype. RESULTS Aberrant T cells were detected by FC in 18 of 33 SBB specimens, of which all had clinicomorphologic features of MF. Of the remaining 15 SSB specimens, six had clinicomorphologic features of MF and nine were diagnosed with benign inflammatory dermatoses. Unexpectedly, CD26 was aberrantly overexpressed in 11 (73%) and lost in three (20%) of 15 SSB specimens from patients with MF where this antigen was evaluated. Other detected aberrancies included CD3 dim- (13/18 [72%]), CD7 dim- (15/18 [83%]), and CD4-/CD8- (3/18 [17%]). CONCLUSIONS FC is capable of identifying putative neoplastic cells on SSB specimens from patients with MF. Bright homogeneous CD26 expression is a common and previously undescribed immunophenotypic aberrancy on MF skin infiltrates.
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Affiliation(s)
- Pedro Horna
- Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Danielle Kurant
- The Department of Pathology and Cell Biology, University of South Florida, Tampa
| | - Lubomir Sokol
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL
| | | | - Lynn Moscinski
- Department of Hematopathology and Laboratory Medicine, H. Lee Moffitt Cancer Center, Tampa, FL
| | - L. Frank Glass
- Department of Dermatology, H. Lee Moffitt Cancer Center, Tampa, FL
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38
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Polansky M, Talpur R, Daulat S, Hosing C, Dabaja B, Duvic M. Long-Term Complete Responses to Combination Therapies and Allogeneic Stem Cell Transplants in Patients With Sézary Syndrome. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2015; 15:e83-93. [DOI: 10.1016/j.clml.2014.09.013] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 09/26/2014] [Accepted: 09/30/2014] [Indexed: 10/24/2022]
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39
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Shiue LH, Couturier J, Lewis DE, Wei C, Ni X, Duvic M. The effect of extracorporeal photopheresis alone or in combination therapy on circulating CD4(+) Foxp3(+) CD25(-) T cells in patients with leukemic cutaneous T-cell lymphoma. PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE 2015; 31:184-94. [PMID: 25772268 DOI: 10.1111/phpp.12175] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/08/2015] [Indexed: 01/04/2023]
Abstract
PURPOSE Extracorporeal photopheresis (ECP) alone or in combination therapy is effective for treatment of leukemic cutaneous T-cell lymphoma (L-CTCL), but its mechanism(s) of action remain unclear. This study was designed to investigate the effect of ECP on regulatory T cells and CD8(+) T cells in L-CTCL patients. EXPERIMENTAL DESIGN Peripheral blood from 18 L-CTCL patients at baseline, Day 2, 1 month, 3 month, and 6 month post-ECP therapy was analyzed by flow cytometry for CD4(+) CD25(+/high) , CD4(+) Foxp3(+) CD25(+/-) , CD3(+) CD8(+) , CD3(+) CD8(+) CD69(+) , and CD3(+) CD8(+) IFN-γ(+) T cells. Clinical responses were assessed and correlated with changes in these T-cell subsets. RESULTS Twelve of 18 patients achieved clinical responses. The average baseline number of CD4(+) CD25(+/high) T cells of PBMCs in L-CTCL patients was normal (2.2%), but increased at 6-month post-therapy (4.3%, P < 0.01). The average baseline number of CD4(+) Foxp3(+) T cells out of CD4(+) T cells in nine evaluable patients was high (66.8 ± 13.7%), mostly CD25 negative. The levels of CD4(+) Foxp3(+) T cells in responders were higher (n = 6, 93.1 ± 5.7%) than nonresponders (n = 3, 14.2 ± 16.0%, P < 0.01), and they declined in parallel with malignant T cells. The numbers of CD3(+) CD8(+) CD69(+) and CD3(+) CD8(+) IFN-γ(+) T cells increased at 3-month post-therapy in five of six patients studied. CONCLUSIONS Extracorporeal photopheresis alone or in combination therapy might be effective in L-CTCL patients whose malignant T cells have a CD4(+) Foxp3(+) CD25(-) phenotype.
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Affiliation(s)
- Lisa H Shiue
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Graduate Program in Immunology, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jacob Couturier
- Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.,Graduate Program in Virology, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Dorothy E Lewis
- Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.,Graduate Program in Virology, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Caimiao Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiao Ni
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Graduate Program in Immunology, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Madeleine Duvic
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Graduate Program in Immunology, Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA
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Single TCR-Vβ2 evaluation discloses the circulating T cell clone in Sezary syndrome: one family fits all! Arch Dermatol Res 2015; 307:487-93. [DOI: 10.1007/s00403-015-1548-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 01/26/2015] [Accepted: 02/05/2015] [Indexed: 01/16/2023]
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Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood 2015; 125:1883-9. [PMID: 25605368 DOI: 10.1182/blood-2014-09-600924] [Citation(s) in RCA: 180] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sézary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-cell lymphoma patients. This trial was registered at www.clinicaltrials.gov as #NCT00888927.
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Vandersee S, Humme D, Terhorst D, Almohamad A, Möbs M, Beyer M. Evaluation of blood parameters for the monitoring of erythrodermic cutaneous T-cell lymphoma. J Dtsch Dermatol Ges 2015; 13:30-6. [DOI: 10.1111/ddg.12549] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Staffan Vandersee
- Skin cancer centre Charité, Department of Dermatology and Allergy, Charité -Universitätsmedizin Berlin; Berlin Germany
| | - Daniel Humme
- Skin cancer centre Charité, Department of Dermatology and Allergy, Charité -Universitätsmedizin Berlin; Berlin Germany
| | - Dorothea Terhorst
- Skin cancer centre Charité, Department of Dermatology and Allergy, Charité -Universitätsmedizin Berlin; Berlin Germany
| | - Anis Almohamad
- Department of Lasermedicine, Elisabeth-Klinikum; Berlin Germany
| | - Markus Möbs
- Skin cancer centre Charité, Department of Dermatology and Allergy, Charité -Universitätsmedizin Berlin; Berlin Germany
| | - Marc Beyer
- Skin cancer centre Charité, Department of Dermatology and Allergy, Charité -Universitätsmedizin Berlin; Berlin Germany
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Novelli M, Fava P, Sarda C, Ponti R, Osella-Abate S, Savoia P, Bergallo M, Lisa F, Fierro MT, Quaglino P. Blood flow cytometry in Sézary syndrome: new insights on prognostic relevance and immunophenotypic changes during follow-up. Am J Clin Pathol 2015; 143:57-69. [PMID: 25511143 DOI: 10.1309/ajcp1na3ychcdeig] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Abstract
OBJECTIVES Sézary syndrome (SS) is characterized by erythroderma, generalized lymphadenopathy, and the presence of circulating atypical lymphocytes, which are difficult to identify by morphologic data. METHODS We revised our series of 107 patients in an attempt to better define the phenotypic aberrancies in blood at diagnosis and the immunophenotypic stability over time detected by flow cytometry. Polymerase chain reaction assay was also used to study CD26/dipeptidyl peptidase IV (DPPIV) gene methylation. RESULTS The most common aberrancies were represented by the lack of CD26 (96/107) or CD38 (101/107) expression and the presence of a "dim" CD3, CD4, or CD2 population. There was a high variability in CD7 expression. In total, 31% of the patients had phenotypical heterogeneity in CD26 and CD7 expression at diagnosis. The phenotype was stable over time in 73 of 95 patients with available follow-up data, while 22 of 95 patients developed changes in CD26, CD7, or CD2 expression. CD4+CD26- SS showed hypermethylation of the CpG islands for the promoter region of CD26/DPPIV. Multivariate analysis showed that CD26 expression is a favorable prognostic factor (hazard ratio, 2.94; P = .045). CONCLUSIONS We confirm the relevance of CD26 negativity in SS diagnosis and monitoring. Nevertheless, the presence of rare CD26+ cases suggests that a multiparameter flow cytometry approach should be used. Changes in methylation profile could account for phenotypical heterogeneity.
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Affiliation(s)
- Mauro Novelli
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Paolo Fava
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Cristina Sarda
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Renata Ponti
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Simona Osella-Abate
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Paola Savoia
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
| | | | - Francesco Lisa
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Maria Teresa Fierro
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Pietro Quaglino
- Dermatologic Clinic, Department of Medical Sciences, University of Torino, Torino, Italy
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Vandersee S, Humme D, Terhorst D, Almohamad A, Möbs M, Beyer M. Evaluation von Laborparametern für das Monitoring bei erythrodermischen kutanen T-Zell-Lymphomen. J Dtsch Dermatol Ges 2015. [DOI: 10.1111/ddg.12549_suppl] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Staffan Vandersee
- Dermatoonkologisches Zentrum der Charité, Klinik für Dermatologie, Allergologie und Venerologie, Charité - Universitätsmedizin Berlin
| | - Daniel Humme
- Dermatoonkologisches Zentrum der Charité, Klinik für Dermatologie, Allergologie und Venerologie, Charité - Universitätsmedizin Berlin
| | - Dorothea Terhorst
- Dermatoonkologisches Zentrum der Charité, Klinik für Dermatologie, Allergologie und Venerologie, Charité - Universitätsmedizin Berlin
| | | | - Markus Möbs
- Dermatoonkologisches Zentrum der Charité, Klinik für Dermatologie, Allergologie und Venerologie, Charité - Universitätsmedizin Berlin
| | - Marc Beyer
- Dermatoonkologisches Zentrum der Charité, Klinik für Dermatologie, Allergologie und Venerologie, Charité - Universitätsmedizin Berlin
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Abstract
T-cell lymphomas are a group of predominantly rare hematologic malignancies that tend to recapitulate different stages of T-cell development, in a similar way that B-cell lymphomas do. As opposed to B-cell lymphomas, the understanding of the biology and the classification of T-cell lymphomas are somewhat rudimentary, and numerous entities are still included as 'provisional categories' in the World Health Classification of hematolopoietic malignancies. A relevant and useful classification of these disorders have been difficult to accomplish because of the rarity nature of them, the relative lack of understanding of the molecular pathogenesis, and their morphological and immunophenotypical complexity. Overall, T-cell lymphomas represent only 15 % of all non-Hodgkin lymphomas. This review is focused on addressing the current status of the categories of mature T-cell leukemias and lymphomas (nodal and extranodal) using an approach that incorporates histopathology, immunophenotype, and molecular understanding of the nature of these disorders, using the same philosophy of the most recent revised WHO classification of hematopoietic malignancies.
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Affiliation(s)
- Alejandro Ariel Gru
- Department of Pathology and Dermatology, Divisions of Hematopathology and Dermatopathology, Cutaneous Lymphoma Program, The Ohio State University Wexner Medical Center, Richard Solove 'The James' Comprehensive Cancer Center, 333 W 10th Ave, Columbus, OH, 43210, USA,
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Ni X, Jorgensen JL, Goswami M, Challagundla P, Decker WK, Kim YH, Duvic MA. Reduction of Regulatory T Cells by Mogamulizumab, a Defucosylated Anti-CC Chemokine Receptor 4 Antibody, in Patients with Aggressive/Refractory Mycosis Fungoides and Sézary Syndrome. Clin Cancer Res 2014; 21:274-85. [DOI: 10.1158/1078-0432.ccr-14-0830] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Dulmage BO, Geskin LJ. Lessons learned from gene expression profiling of cutaneous T-cell lymphoma. Br J Dermatol 2014; 169:1188-97. [PMID: 23937674 DOI: 10.1111/bjd.12578] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2013] [Indexed: 12/14/2022]
Abstract
Gene expression studies of cutaneous T-cell lymphoma (CTCL) span a decade, yet the pathogenesis is poorly understood and diagnosis remains a challenge. This review examines the varied approaches to gene expression analysis of CTCL, with emphasis on cell populations, control selection and expression data collection. Despite discordant results, several dysregulated genes have been identified across multiple studies, including PLS3, KIR3DL2, TWIST1 and STAT4. Here, we provide an overview of the most consistently expressed genes across different studies and bring them together through common pathways biologically relevant to CTCL. Four pathways - evasion of activation-induced cell death, T helper 2 lymphocyte differentiation, transforming growth factor-β receptor expression, and tumour necrosis factor receptor ligands - appear to encompass the most frequently affected genes, hypothetically providing insight into the disease pathogenesis.
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Affiliation(s)
- B O Dulmage
- Department of Dermatology, University of Pittsburgh, 200 Lothrop St, Pittsburgh, PA, 15213, U.S.A
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48
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Wilcox RA. Cutaneous T-cell lymphoma: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 2014; 89:837-51. [PMID: 25042790 DOI: 10.1002/ajh.23756] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 04/29/2014] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Cutaneous T-cell lymphomas are a heterogenous group of T-cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). DIAGNOSIS The diagnosis of MF or SS requires the integration of clinical and histopathologic data. RISK-ADAPTED THERAPY TNMB (tumor, node, metastasis, and blood) staging remains the most important prognostic factor in MF/SS and forms the basis for a "risk-adapted," multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin-directed therapies is preferred, as both disease-specific and overall survival for these patients is favorable. In contrast, patients with advanced-stage disease with significant nodal, visceral or blood involvement are generally approached with biologic-response modifiers or histone deacetylase inhibitors prior to escalating therapy to include systemic, single-agent chemotherapy. Multiagent chemotherapy (e.g., CHOP) may be employed for those patients with extensive visceral involvement requiring rapid disease control. In highly selected patients, allogeneic stem-cell transplantation may be considered.
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Affiliation(s)
- Ryan A. Wilcox
- Division of Hematology/Oncology; University of Michigan Cancer Center; Ann Arbor Michigan
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Scarisbrick J, Kim Y, Whittaker S, Wood G, Vermeer M, Prince H, Quaglino P. Prognostic factors, prognostic indices and staging in mycosis fungoides and Sézary syndrome: where are we now? Br J Dermatol 2014; 170:1226-36. [DOI: 10.1111/bjd.12909] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2014] [Indexed: 12/28/2022]
Affiliation(s)
- J.J. Scarisbrick
- Department of Dermatology; University Hospital Birmingham; Birmingham U.K
| | - Y.H. Kim
- Stanford Cancer Centre & School of Medicine; Stanford CA U.S.A
| | - S.J. Whittaker
- Department of Dermatology; Guy's and St Thomas' NHS Trust; London U.K
| | - G.S. Wood
- Department of Dermatology; University of Wisconsin and Middleton VA Medical Center; Madison WI U.S.A
| | - M.H. Vermeer
- Department of Dermatology; Leiden University Medical Centre; Leiden the Netherlands
| | - H.M. Prince
- Peter MacCallum Cancer Centre and University of Melbourne; Melbourne VIC Australia
| | - P. Quaglino
- Department of Medical Sciences; Dermatologic Clinic; University of Torino; Turin Italy
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50
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Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome). J Am Acad Dermatol 2014; 70:205.e1-16; quiz 221-2. [DOI: 10.1016/j.jaad.2013.07.049] [Citation(s) in RCA: 238] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 06/25/2013] [Accepted: 07/01/2013] [Indexed: 02/08/2023]
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