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Olesen CM, Edslev SM, Aasbjerg GN, Yüksel YT, Agner T, Kamstrup MR. Subtype Specific Alterations in the Skin Microbiome of Patients with Cutaneous T-Cell Lymphoma. J Invest Dermatol 2025:S0022-202X(25)00032-6. [PMID: 39848566 DOI: 10.1016/j.jid.2025.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/16/2024] [Accepted: 01/05/2025] [Indexed: 01/25/2025]
Affiliation(s)
- Caroline Meyer Olesen
- Department of Dermato-venereology, Bispebjerg Hospital, University of Copenhagen, Denmark.
| | - Sofie Marie Edslev
- Department of Bioinformatics, Statens Serum Institute, Copenhagen, Denmark
| | | | - Yasemin Topal Yüksel
- Department of Dermato-venereology, Bispebjerg Hospital, University of Copenhagen, Denmark
| | - Tove Agner
- Department of Dermato-venereology, Bispebjerg Hospital, University of Copenhagen, Denmark
| | - Maria Rørbæk Kamstrup
- Department of Dermato-venereology, Bispebjerg Hospital, University of Copenhagen, Denmark
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2
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St. Thomas N, Christopher BN, Reyes L, Robinson RM, Golick L, Zhu X, Chapman E, Dolloff NG. Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma. Biomolecules 2025; 15:76. [PMID: 39858470 PMCID: PMC11763779 DOI: 10.3390/biom15010076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 01/27/2025] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body's surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induction of the HSP70 family member HSPA6 (HSP70B') and, to a lesser extent, HSPA5 (BiP/GRP78). To understand the significance of these two factors, we used a novel isoform selective small-molecule inhibitor of HSPA5/6 (JG-023). JG-023 induced pro-apoptotic UPR signaling and enhanced the cytotoxic effects of proteasome inhibitors and other UPR-inducing drugs in CTCL but not normal T cells. Interestingly, JG-023 also selectively suppressed the production of Th2 cytokines in CTCL and normal CD4+ T cells. Conditioned media (CM) from CTCL were immunosuppressive to normal T cells through an IL-10-dependent mechanism. This immunosuppression could be reversed by JG-023, other HSP70 inhibitors, Btz, and combinations of these UPR-targeted drugs. Our study points to the importance of the UPR in the pathology of CTCL and demonstrates the potential of proteasome and targeted HSPA5/6 inhibitors for therapy.
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Affiliation(s)
- Nadia St. Thomas
- Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA; (N.S.T.); (B.N.C.); (L.R.); (R.M.R.); (L.G.)
| | - Benjamin N. Christopher
- Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA; (N.S.T.); (B.N.C.); (L.R.); (R.M.R.); (L.G.)
| | - Leticia Reyes
- Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA; (N.S.T.); (B.N.C.); (L.R.); (R.M.R.); (L.G.)
| | - Reeder M. Robinson
- Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA; (N.S.T.); (B.N.C.); (L.R.); (R.M.R.); (L.G.)
| | - Lena Golick
- Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA; (N.S.T.); (B.N.C.); (L.R.); (R.M.R.); (L.G.)
| | - Xiaoyi Zhu
- Department of Pharmacology and Therapeutics, Center for Inflammation Science and Systems Medicine, University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA; (X.Z.); (E.C.)
| | - Eli Chapman
- Department of Pharmacology and Therapeutics, Center for Inflammation Science and Systems Medicine, University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USA; (X.Z.); (E.C.)
| | - Nathan G. Dolloff
- Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USA; (N.S.T.); (B.N.C.); (L.R.); (R.M.R.); (L.G.)
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- Zucker Institute for Innovation Commercialization, Charleston, SC 29425, USA
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3
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Wen P, Zhuo X, Wang L. Skin barrier dysfunction in cutaneous T-cell lymphoma: From pathogenic mechanism of barrier damage to treatment. Crit Rev Oncol Hematol 2025; 205:104559. [PMID: 39549893 DOI: 10.1016/j.critrevonc.2024.104559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 10/30/2024] [Accepted: 11/08/2024] [Indexed: 11/18/2024] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a group of non-Hodgkin lymphomas characterized by multiple erythematous patches, plaques, or even nodules on the skin. As the disease progresses, patients develop widespread pruritic skin lesions, leading to skin barrier dysfunction, which significantly impacts their quality of life, appearance, and social adaptation. The pathogenesis of CTCL is not fully understood. Recent studies have recognized the important role of skin barrier dysfunction in the development and progression of CTCL, yet a comprehensive review on this topic is lacking. This review summarizes recent findings on skin barrier dysfunction in CTCL, focusing on physical barrier dysfunction, chronic inflammation, and immune dysregulation. We also discuss current and potential therapies aimed at restoring barrier function in CTCL. By emphasizing the integration of barrier-centric approaches into CTCL management, this review provides valuable insights for improving treatment outcomes.
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Affiliation(s)
- Pengfei Wen
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
| | - Xiaoxue Zhuo
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
| | - Lin Wang
- Department of Dermatology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China.
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4
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Huang TC, Chang CH, Hsiao PF, Hsu CK, Lin CY, Wu CS, Yeh SP, Tsai TF. Cutaneous T-cell lymphoma: Consensus on diagnosis and management in Taiwan. J Formos Med Assoc 2024:S0929-6646(24)00517-5. [PMID: 39496538 DOI: 10.1016/j.jfma.2024.11.001] [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: 08/26/2024] [Revised: 10/17/2024] [Accepted: 11/01/2024] [Indexed: 11/06/2024] Open
Abstract
Cutaneous T cell lymphomas (CTCLs), with mycosis fungoides (MF) and Sézary syndrome (SS) as the classic types, are the commonest group of primary cutaneous lymphomas. The diverse clinical manifestation and non-specific histologic findings of early lesions in CTCLs render diagnosis challenging. Treatment modalities also vary and include topical and oral medications, chemotherapy, phototherapy, and radiation therapies. Local dermatological, hemato-oncologic and radiotherapeutical experts in Taiwan convened meetings in 2023 to review and discuss the latest evidence and updates regarding diagnosis and management of CTCLs. A consensus was developed with the aim to raise awareness and understanding, provide practical guidance for early diagnosis and appropriate management, and ultimately optimize care to maximize benefits of patients.
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Affiliation(s)
- Tai-Chung Huang
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chung-Hsing Chang
- Skin Institute, Department of Dermatology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Pa-Fan Hsiao
- Department of Dermatology, MacKay Memorial Hospital, Taipei, Taiwan; Department of Medicine, MacKay Medical College, New Taipei City, Taiwan; MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan
| | - Chao-Kai Hsu
- Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chien-Yio Lin
- Department of Dermatology, Chang Gung Memorial Hospital, Linkou and Taipei, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chien-Shan Wu
- Department of Dermatology, Pingtung Veterans General Hospital, Pingtung, Taiwan
| | - Su-Peng Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; China Medical University, Taichung, Taiwan
| | - Tsen-Fang Tsai
- Department of Dermatology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
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5
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Pang Y, Nguyen WQ, Guerrero LI, Chrisman LP, Hooper MJ, McCarthy MC, Hales MK, Lipman RE, Paller AS, Guitart J, Zhou XA. Deciphering the Etiologies of Adult Erythroderma: An Updated Guide to Presentations, Diagnostic Tools, Pathophysiologies, and Treatments. Am J Clin Dermatol 2024; 25:927-950. [PMID: 39348008 DOI: 10.1007/s40257-024-00886-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2024] [Indexed: 10/01/2024]
Abstract
Erythroderma, an inflammatory skin condition characterized by widespread erythema with variable degrees of exfoliation, pustulation, or vesiculobullous formation, is associated with high morbidity and mortality. Determining the underlying cause of erythroderma frequently presents a diagnostic challenge, which may contribute to the condition's relatively poor prognosis. This review covers the clinical presentation, pathophysiology, diagnosis, and treatment of erythroderma. It discusses similarities and differences among the many underlying etiologies of the condition and differences between erythrodermic and non-erythrodermic presentations of the same dermatosis. Finally, this article explores current research that may provide future tools in the diagnosis and management of erythroderma.
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Affiliation(s)
- Yanzhen Pang
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - William Q Nguyen
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Liliana I Guerrero
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - Lauren P Chrisman
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - Madeline J Hooper
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - Morgan C McCarthy
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - Molly K Hales
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - Rachel E Lipman
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - Amy S Paller
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - Joan Guitart
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA
| | - Xiaolong A Zhou
- Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 N Saint Clair, Arkes 1600, Chicago, IL, 60611, USA.
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6
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Gordon ER, Fahmy LM, Trager MH, Adeuyan O, Lapolla BA, Schreidah CM, Geskin LJ. From Molecules to Microbes: Tracing Cutaneous T-Cell Lymphoma Pathogenesis through Malignant Inflammation. J Invest Dermatol 2024; 144:1954-1962. [PMID: 38703171 DOI: 10.1016/j.jid.2024.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/14/2024] [Accepted: 03/16/2024] [Indexed: 05/06/2024]
Abstract
The etiology of CTCL is a subject of extensive investigation. Researchers have explored links between CTCL and environmental chemical exposures, such as aromatic hydrocarbons (eg, pesticides and benzene), as well as infectious factors, including various viruses (eg, human T-lymphotropic virus [HTLV]-I and HTLV-II) and bacteria (eg, Staphylococcus aureus). There has been growing emphasis on the role of malignant inflammation in CTCL development. In this review, we synthesize studies of environmental and infectious exposures, along with research on the aryl hydrocarbon receptor and the involvement of pathogens in disease etiology, providing insight into the pathogenesis of CTCL.
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Affiliation(s)
- Emily R Gordon
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Lauren M Fahmy
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Megan H Trager
- Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA
| | - Oluwaseyi Adeuyan
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Brigit A Lapolla
- Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA
| | - Celine M Schreidah
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Larisa J Geskin
- Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA; Department of Dermatology, Columbia University Irving Medical Center, New York, New York, USA.
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7
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Licht P, Dominelli N, Kleemann J, Pastore S, Müller ES, Haist M, Hartmann KS, Stege H, Bros M, Meissner M, Grabbe S, Heermann R, Mailänder V. The skin microbiome stratifies patients with cutaneous T cell lymphoma and determines event-free survival. NPJ Biofilms Microbiomes 2024; 10:74. [PMID: 39198450 PMCID: PMC11358159 DOI: 10.1038/s41522-024-00542-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 07/31/2024] [Indexed: 09/01/2024] Open
Abstract
Mycosis fungoides (MF) is the most common entity of Cutaneous T cell lymphomas (CTCL) and is characterized by the presence of clonal malignant T cells in the skin. The role of the skin microbiome for MF development and progression are currently poorly understood. Using shotgun metagenomic profiling, real-time qPCR, and T cell receptor sequencing, we compared lesional and nonlesional skin of 20 MF patients with early and advanced MF. Additionally, we isolated Staphylococcus aureus and other bacteria from MF skin for functional profiling and to study the S. aureus virulence factor spa. We identified a subgroup of MF patients with substantial dysbiosis on MF lesions and concomitant outgrowth of S. aureus on plaque-staged lesions, while the other MF patients had a balanced microbiome on lesional skin. Dysbiosis and S. aureus outgrowth were accompanied by ectopic levels of cutaneous antimicrobial peptides (AMPs), including adaptation of the plaque-derived S. aureus strain. Furthermore, the plaque-derived S. aureus strain showed a reduced susceptibility towards antibiotics and an upregulation of the virulence factor spa, which may activate the NF-κB pathway. Remarkably, patients with dysbiosis on MF lesions had a restricted T cell receptor repertoire and significantly lower event-free survival. Our study highlights the potential for microbiome-modulating treatments targeting S. aureus to prevent MF progression.
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Affiliation(s)
- Philipp Licht
- University Medical Centre Mainz, Department of Dermatology, Mainz, Germany.
| | - Nazzareno Dominelli
- Johannes Gutenberg-University, Institute of Molecular Physiology (imP), Biocenter II, Microbiology and Biotechnology, Mainz, Germany
| | - Johannes Kleemann
- University Hospital Frankfurt, Department of Dermatology, Venerology and Allergology, Frankfurt am Main, Germany
| | - Stefan Pastore
- University Medical Centre Mainz, Institute of Human Genetics, Mainz, Germany
- Johannes Gutenberg-University, Institute of Pharmaceutical and Biomedical Sciences, Mainz, Germany
| | - Elena-Sophia Müller
- Johannes Gutenberg-University, Institute of Molecular Physiology (imP), Biocenter II, Microbiology and Biotechnology, Mainz, Germany
| | - Maximilian Haist
- University Medical Centre Mainz, Department of Dermatology, Mainz, Germany
| | | | - Henner Stege
- University Medical Centre Mainz, Department of Dermatology, Mainz, Germany
| | - Matthias Bros
- University Medical Centre Mainz, Department of Dermatology, Mainz, Germany
| | - Markus Meissner
- University Hospital Frankfurt, Department of Dermatology, Venerology and Allergology, Frankfurt am Main, Germany
| | - Stephan Grabbe
- University Medical Centre Mainz, Department of Dermatology, Mainz, Germany
| | - Ralf Heermann
- Johannes Gutenberg-University, Institute of Molecular Physiology (imP), Biocenter II, Microbiology and Biotechnology, Mainz, Germany
| | - Volker Mailänder
- University Medical Centre Mainz, Department of Dermatology, Mainz, Germany.
- Max Planck Institute for Polymer Research, Mainz, Germany.
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8
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Wojewoda K, Gillstedt M, Lewerin C, Osmancevic A. Sézary Syndrome in West Sweden: Exploring Epidemiology, Clinical Features, and Treatment Patterns in a Registry-Based Retrospective Analysis. Cancers (Basel) 2024; 16:1948. [PMID: 38893069 PMCID: PMC11171299 DOI: 10.3390/cancers16111948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/17/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
Sézary syndrome (SS) is a rare primary cutaneous T-cell lymphoma variant. Despite various treatment options, it remains incurable, with a poor prognosis. There is an urgent need for additional descriptive research to enhance our understanding and treatment of SS. The aim of this retrospective register-based study was to outline patients' demographic characteristics; investigate the clinical, histopathological, and molecular findings; and assess treatment effectiveness with a focus on time to next treatment (TTNT) and disease progression. Data on 17 patients with SS were obtained from the primary cutaneous lymphoma register in West Sweden between 2012 and 2024. The results revealed that not all patients exhibited the classical triad of symptoms at diagnosis, emphasizing the need for personalized diagnostic approaches. The median survival was only 2.1 years, which reflects the aggressive nature of SS. The longest median TTNT was observed in triple therapy involving retinoids, interferon alpha, and extracorporeal photopheresis (ECP). There was no significant difference in TTNT between various lines of treatment. Early initiation of ECP treatment did not result in improved outcomes. This study highlights the importance of combination therapy for improved outcomes and underscores the need for future studies to identify optimal treatment approaches.
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Affiliation(s)
- Karolina Wojewoda
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden; (M.G.); (A.O.)
- Region Västra Götaland, Department of Dermatology and Venereology, Sahlgrenska University Hospital, 413 46 Gothenburg, Sweden
| | - Martin Gillstedt
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden; (M.G.); (A.O.)
- Region Västra Götaland, Department of Dermatology and Venereology, Sahlgrenska University Hospital, 413 46 Gothenburg, Sweden
| | - Catharina Lewerin
- Section of Hematology and Coagulation, Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden;
| | - Amra Osmancevic
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden; (M.G.); (A.O.)
- Region Västra Götaland, Department of Dermatology and Venereology, Sahlgrenska University Hospital, 413 46 Gothenburg, Sweden
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9
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Zeng Z, Vadivel CK, Gluud M, Namini MRJ, Yan L, Ahmad S, Hansen MB, Coquet J, Mustelin T, Koralov SB, Bonefeld CM, Woetmann A, Geisler C, Guenova E, Kamstrup MR, Litman T, Gjerdrum LMR, Buus TB, Ødum N. Keratinocytes Present Staphylococcus aureus Enterotoxins and Promote Malignant and Nonmalignant T Cell Proliferation in Cutaneous T-Cell Lymphoma. J Invest Dermatol 2024:S0022-202X(24)00377-4. [PMID: 38762064 DOI: 10.1016/j.jid.2024.04.018] [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: 02/05/2024] [Revised: 04/06/2024] [Accepted: 04/09/2024] [Indexed: 05/20/2024]
Abstract
Cutaneous T-cell lymphoma is characterized by malignant T cells proliferating in a unique tumor microenvironment dominated by keratinocytes (KCs). Skin colonization and infection by Staphylococcus aureus are a common cause of morbidity and are suspected of fueling disease activity. In this study, we show that expression of HLA-DRs, high-affinity receptors for staphylococcal enterotoxins (SEs), by KCs correlates with IFN-γ expression in the tumor microenvironment. Importantly, IFN-γ induces HLA-DR, SE binding, and SE presentation by KCs to malignant T cells from patients with Sézary syndrome and malignant and nonmalignant T-cell lines derived from patients with Sézary syndrome and mycosis fungoides. Likewise, preincubation of KCs with supernatant from patient-derived SE-producing S aureus triggers proliferation in malignant T cells and cytokine release (including IL-2), when cultured with nonmalignant T cells. This is inhibited by pretreatment with engineered bacteriophage S aureus-specific endolysins. Furthermore, alteration in the HLA-DR-binding sites of SE type A and small interfering RNA-mediated knockdown of Jak3 and IL-2Rγ block induction of malignant T-cell proliferation. In conclusion, we show that upon exposure to patient-derived S aureus and SE, KCs stimulate IL-2Rγ/Jak3-dependent proliferation of malignant and nonmalignant T cells in an environment with nonmalignant T cells. These findings suggest that KCs in the tumor microenvironment play a key role in S aureus-mediated disease activity in cutaneous T-cell lymphoma.
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Affiliation(s)
- Ziao Zeng
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Chella Krishna Vadivel
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Maria Gluud
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Martin R J Namini
- 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
| | - Sana Ahmad
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Morten Bagge Hansen
- Blood Bank, Department of Clinical Immunology, State University Hospital (Rigshospitalet), Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jonathan Coquet
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Tomas Mustelin
- Department of Rheumatology, University of Washington, Seattle, Washington, USA
| | - Sergei B Koralov
- Department of Pathology, New York University School of Medicine, New York, New York, USA
| | - Charlotte Menne Bonefeld
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Anders Woetmann
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Geisler
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Emmanuella Guenova
- University Hospital Lausanne (CHUV), Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Maria R Kamstrup
- Department of Dermatology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark
| | - Thomas Litman
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Lise-Mette R Gjerdrum
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pathology, Zealand University Hospital, Roskilde, Roskilde, Denmark
| | - Terkild B Buus
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
| | - Niels Ødum
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
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10
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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: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [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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11
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Dey S, Vieyra-Garcia PA, Joshi AA, Trajanoski S, Wolf P. Modulation of the skin microbiome in cutaneous T-cell lymphoma delays tumour growth and increases survival in the murine EL4 model. Front Immunol 2024; 15:1255859. [PMID: 38646524 PMCID: PMC11026597 DOI: 10.3389/fimmu.2024.1255859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 03/21/2024] [Indexed: 04/23/2024] Open
Abstract
Cutaneous T-cell lymphomas (CTCL) are a group of lymphoproliferative disorders of skin-homing T cells causing chronic inflammation. These disorders cause impairment of the immune environment, which leads to severe infections and/or sepsis due to dysbiosis. In this study, we elucidated the host-microbial interaction in CTCL that occurs during the phototherapeutic treatment regime and determined whether modulation of the skin microbiota could beneficially affect the course of CTCL. EL4 T-cell lymphoma cells were intradermally grafted on the back of C57BL/6 mice. Animals were treated with conventional therapeutics such as psoralen + UVA (PUVA) or UVB in the presence or absence of topical antibiotic treatment (neomycin, bacitracin, and polymyxin B sulphate) as an adjuvant. Microbial colonisation of the skin was assessed to correlate with disease severity and tumour growth. Triple antibiotic treatment significantly delayed tumour occurrence (p = 0.026), which prolonged the survival of the mice (p = 0.033). Allocation to phototherapeutic agents PUVA, UVB, or none of these, along with antibiotic intervention, reduced the tumour growth significantly (p = 0.0327, p ≤ 0.0001, p ≤ 0.0001 respectively). The beta diversity indices calculated using the Bray-Curtis model showed that the microbial population significantly differed after antibiotic treatment (p = 0.001). Upon modulating the skin microbiome by antibiotic treatment, we saw an increase in commensal Clostridium species, e.g., Lachnospiraceae sp. (p = 0.0008), Ruminococcaceae sp. (p = 0.0001)., Blautia sp. (p = 0.007) and a significant reduction in facultative pathogens Corynebacterium sp. (p = 0.0009), Pelomonas sp. (p = 0.0306), Streptococcus sp. (p ≥ 0.0001), Pseudomonas sp. (p = 0.0358), and Cutibacterium sp. (p = 0.0237). Intriguingly, we observed a significant decrease in Staphylococcus aureus frequency (p = 0.0001) but an increase in the overall detection frequency of the Staphylococcus genus, indicating that antibiotic treatment helped regain the microbial balance and increased the number of non-pathogenic Staphylococcus populations. These study findings show that modulating microbiota by topical antibiotic treatment helps to restore microbial balance by diminishing the numbers of pathogenic microbes, which, in turn, reduces chronic inflammation, delays tumour growth, and increases survival rates in our CTCL model. These findings support the rationale to modulate the microbial milieu during the disease course of CTCL and indicate its therapeutic potential.
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MESH Headings
- Animals
- Microbiota/drug effects
- Mice
- Skin/microbiology
- Skin/pathology
- Skin/immunology
- Skin/drug effects
- Skin Neoplasms/microbiology
- Skin Neoplasms/immunology
- Skin Neoplasms/pathology
- Lymphoma, T-Cell, Cutaneous/microbiology
- Lymphoma, T-Cell, Cutaneous/pathology
- Lymphoma, T-Cell, Cutaneous/drug therapy
- Lymphoma, T-Cell, Cutaneous/therapy
- Mice, Inbred C57BL
- Disease Models, Animal
- Anti-Bacterial Agents/therapeutic use
- Anti-Bacterial Agents/pharmacology
- Anti-Bacterial Agents/administration & dosage
- Cell Line, Tumor
- Female
- Humans
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Affiliation(s)
- Saptaswa Dey
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | | | - Aaroh Anand Joshi
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Slave Trajanoski
- Core Facility Computational Bioanalytics, Medical University of Graz, Graz, Austria
| | - Peter Wolf
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
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12
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Abdi A, Oroojzadeh P, Valivand N, Sambrani R, Lotfi H. Immunological aspects of probiotics for improving skin diseases: Influence on the Gut-Brain-Skin Axis. Biochem Biophys Res Commun 2024; 702:149632. [PMID: 38340656 DOI: 10.1016/j.bbrc.2024.149632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/27/2024] [Accepted: 02/04/2024] [Indexed: 02/12/2024]
Abstract
The interplay between gut microbiota and human health, both mental and physical, is well-documented. This connection extends to the gut-brain-skin axis, linking gut microbiota to skin health. Recent studies have underscored the potential of probiotics and prebiotics to modulate gut microbiota, supported by in vivo and clinical investigations. In this comprehensive review, we explore the immunological implications of probiotics in influencing the gut-skin axis for the treatment and prevention of skin conditions, including psoriasis, acne, diabetic ulcers, atopic dermatitis, and skin cancer. Our analysis reveals that probiotics exert their effects by modulating cytokine production, whether administered orally or topically. Probiotics bolster skin defenses through the production of antimicrobial peptides and the induction of keratinocyte differentiation and regeneration. Yet, many questions surrounding probiotics remain unanswered, necessitating further exploration of their mechanisms of action in the context of skin diseases.
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Affiliation(s)
- Ali Abdi
- Medical Immunology, Aziz Sancar Institute of Experimental Medicine, İstanbul University, Istanbul, Turkey
| | - Parvin Oroojzadeh
- Student Research Committee, Department of Food Science and Technology, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nassim Valivand
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Roshanak Sambrani
- Clinical Research Development Unit of Razi Educational and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajie Lotfi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
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13
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Gumina ME, Hooper MJ, Zhou XA, Koralov SB. Role of Antigenic Stimulation in Cutaneous T-Cell Lymphomas. J Invest Dermatol 2024; 144:755-763. [PMID: 38149950 PMCID: PMC10960716 DOI: 10.1016/j.jid.2023.10.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/09/2023] [Accepted: 10/27/2023] [Indexed: 12/28/2023]
Abstract
Cutaneous T-cell lymphoma (CTCL) involves a clonal expansion of malignant cells accumulating in the skin, a primary barrier site. CTCL has long been hypothesized to be caused or perpetuated by chronic antigen stimulation due to unknown exposures. These antigenic triggers, defined as any element that may cause activation of malignant T cells through TCR signaling, have been hypothesized to range from chemicals to microbes. This review covers current evidence supporting chemical and microbial stimuli that may act as antigenic triggers of CTCL and summarizes novel areas of investigation, in which the potential antigenicity of the exposure is still unknown.
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Affiliation(s)
- Megan E Gumina
- Department of Pathology, Grossman School of Medicine, New York University, New York, New York, USA
| | - Madeline J Hooper
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Xiaolong A Zhou
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
| | - Sergei B Koralov
- Department of Pathology, Grossman School of Medicine, New York University, New York, New York, USA.
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14
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Ødum AWF, Geisler C. Vitamin D in Cutaneous T-Cell Lymphoma. Cells 2024; 13:503. [PMID: 38534347 PMCID: PMC10969440 DOI: 10.3390/cells13060503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/05/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is characterized by the proliferation of malignant T cells in inflamed skin lesions. Mycosis fungoides (MF)-the most common variant of CTCL-often presents with skin lesions around the abdomen and buttocks ("bathing suit" distribution), i.e., in skin areas devoid of sun-induced vitamin D. For decades, sunlight and vitamin D have been connected to CTCL. Thus, vitamin D induces apoptosis and inhibits the expression of cytokines in malignant T cells. Furthermore, CTCL patients often display vitamin D deficiency, whereas phototherapy induces vitamin D and has beneficial effects in CTCL, suggesting that light and vitamin D have beneficial/protective effects in CTCL. Inversely, vitamin D promotes T helper 2 (Th2) cell specific cytokine production, regulatory T cells, tolerogenic dendritic cells, as well as the expression of immune checkpoint molecules, all of which may have disease-promoting effects by stimulating malignant T-cell proliferation and inhibiting anticancer immunity. Studies on vitamin D treatment in CTCL patients showed conflicting results. Some studies found positive effects, others negative effects, while the largest study showed no apparent clinical effect. Taken together, vitamin D may have both pro- and anticancer effects in CTCL. The balance between the opposing effects of vitamin D in CTCL is likely influenced by treatment and may change during the disease course. Therefore, it remains to be discovered whether and how the effect of vitamin D can be tilted toward an anticancer response in CTCL.
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Affiliation(s)
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
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15
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Rodríguez Baeza D, Bejarano Antonio L, González de Arriba M, Picó-Monllor JA, Cañueto J, Navarro-Lopez V. Cutaneous T-Cell Lymphoma and Microbiota: Etiopathogenesis and Potential New Therapeutic Targets. Dermatol Res Pract 2024; 2024:9919225. [PMID: 38435536 PMCID: PMC10904680 DOI: 10.1155/2024/9919225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/17/2023] [Accepted: 02/08/2024] [Indexed: 03/05/2024] Open
Abstract
Objective To review the scientific literature related to human microbiota and cutaneous T-cell lymphoma. Methodology. An exploratory and systematic review of the articles retrieved from the bibliographic databases MEDLINE (PubMed), Embase, The Cochrane Library, and Scopus, published in the last 10 years with the following descriptors: "lymphoma, T-cell, cutaneous," "microbiota," "Mycosis Fungoides," "Sézary Syndrome," "lymphoma, primary cutaneous anaplastic large cell," "Lymphomatoid Papulosis" and "Microbiota," "microbiota," "Microbial Community," and "Microbial Communities." Results Of the 87 references retrieved, after applying the inclusion and exclusion criteria, 21 articles were selected. Most studies linking cutaneous T-cell lymphoma and the microbiota focus on the cutaneous microbiome, with Staphylococcus aureus being the main related agent. Skin colonization by this bacterium could be involved in the hyperactivation of the STAT3 inflammatory pathway and in the overproduction of IL-17, both of which are widely related to the development of more aggressive and advanced forms of cutaneous T-cell lymphoma. We also found evidence of a possible relationship between intestinal dysbiosis and the development of cutaneous T-cell lymphoma, observing a decrease in taxonomic variability and an increase in certain genera such as Prevotella in the intestinal microbiome of patients with cutaneous T-cell lymphoma. The possible etiopathogenic mechanism underlying this relationship could be explained by an increase in systemic cytokine release, promoting the hyperactivation of STAT3 at the skin level. Conclusion There appears to be a relationship between cutaneous T-cell lymphoma and the cutaneous and intestinal microbiome, as well as a possible pathophysiological pathway involved. The possible modulation of the cutaneous and intestinal microbiome or the action on the signaling inflammatory pathway, using pharmacological tools such as JAK inhibitors or IL-17 inhibitors in the latter case, could open the possibility for future therapeutic studies for cutaneous T-cell lymphoma.
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Affiliation(s)
- Daniel Rodríguez Baeza
- Dermatology Service, Rio Hortega University Hospital, Calle Dulzaina, 2, Valladolid 47012, Spain
- MiBioPath Research Group, Medicine Faculty, Catholic University of Murcia (UCAM), Av. de los Jerónimos, 135, Murcia 30107, Spain
| | - Lía Bejarano Antonio
- Dermatology Service, Salamanca University Hospital, Paseo de la Transición Española, Salamanca 37007, Spain
| | - Marta González de Arriba
- Dermatology Service, Salamanca University Hospital, Paseo de la Transición Española, Salamanca 37007, Spain
| | - José Antonio Picó-Monllor
- Faculty of Pharmacy, Department of Pharmacology, Pediatrics and Organic Chemistry, Miguel Hernández University of Elche, Ctra. Alicante-Valencia N 332, 03550 Sant Joan Alacant, Alicante, Spain
| | - Javier Cañueto
- Dermatology Service, Salamanca University Hospital, Paseo de la Transición Española, Salamanca 37007, Spain
- IBSAL, Institute of Biomedical Research of Salamanca, P.º de San Vicente, 182, Salamanca 37007, Spain
| | - Vicente Navarro-Lopez
- MiBioPath Research Group, Medicine Faculty, Catholic University of Murcia (UCAM), Av. de los Jerónimos, 135, Murcia 30107, Spain
- Clinical Microbiology and Infectious Disease Unit, Vinalopó University Hospital, c/Tonico Sansano Mora, 14, Elche 03293, Spain
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16
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Angelova A, Rommelaere J, Ungerechts G. The Complex Role of Infectious Agents in Human Cutaneous T-Cell Lymphoma Pathogenesis: From Candidate Etiological Factors to Potential Therapeutics. Pathogens 2024; 13:184. [PMID: 38535528 PMCID: PMC10975429 DOI: 10.3390/pathogens13030184] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/12/2024] [Accepted: 02/13/2024] [Indexed: 02/11/2025] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a devastating, potentially fatal T-lymphocyte malignancy affecting the skin. Despite all efforts, the etiology of this disease remains unknown. Infectious agents have long been suspected as factors or co-factors in CTCL pathogenesis. This review deals with the panel of bacterial and viral pathogens that have been investigated so far in an attempt to establish a potential link between infection/carriage and CTCL development. A special focus is given to a recently discovered human protoparvovirus, namely the cutavirus (CutaV), which has emerged as a plausible CTCL etiological agent. Available evidence in support of this hypothesis as well as alternative interpretations and uncertainties raised by some conflicting data are discussed. The complexity and multifacetedness of the Parvoviridae family of viruses are illustrated by presenting another protoparvovirus, the rat H-1 parvovirus (H-1PV). H-1PV belongs to the same genus as the CutaV but carries considerable potential for therapeutic applications in cutaneous lymphoma.
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Affiliation(s)
- Assia Angelova
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (J.R.); (G.U.)
| | - Jean Rommelaere
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (J.R.); (G.U.)
| | - Guy Ungerechts
- Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; (J.R.); (G.U.)
- Department of Medical Oncology, National Center for Tumor Diseases Heidelberg and Heidelberg University Hospital, 69120 Heidelberg, Germany
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17
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Ren J, Liao X, Lewis JM, Chang J, Qu R, Carlson KR, Foss F, Girardi M. Generation and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy. Nat Commun 2024; 15:519. [PMID: 38225288 PMCID: PMC10789731 DOI: 10.1038/s41467-024-44786-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 01/05/2024] [Indexed: 01/17/2024] Open
Abstract
Current treatments for T cell malignancies encounter issues of disease relapse and off-target toxicity. Using T cell receptor (TCR)Vβ2 as a model, here we demonstrate the rapid generation of an off-the-shelf allogeneic chimeric antigen receptor (CAR)-T platform targeting the clone-specific TCR Vβ chain for malignant T cell killing while limiting normal cell destruction. Healthy donor T cells undergo CRISPR-induced TRAC, B2M and CIITA knockout to eliminate T cell-dependent graft-versus-host and host-versus-graft reactivity. Second generation 4-1BB/CD3zeta CAR containing high affinity humanized anti-Vβ scFv is expressed efficiently on donor T cells via both lentivirus and adeno-associated virus transduction with limited detectable pre-existing immunoreactivity. Our optimized CAR-T cells demonstrate specific and persistent killing of Vβ2+ Jurkat cells and Vβ2+ patient derived malignant T cells, in vitro and in vivo, without affecting normal T cells. In parallel, we generate humanized anti-Vβ2 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) by Fc-engineering for NK cell ADCC therapy.
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Affiliation(s)
- Jingjing Ren
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
| | - Xiaofeng Liao
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
| | - Julia M Lewis
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA
| | - Jungsoo Chang
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA
| | - Rihao Qu
- The Computational Biology and Bioinformatics Program, Yale School of Medicine, New Haven, CT, USA
| | - Kacie R Carlson
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA
| | - Francine Foss
- Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, CT, USA
| | - Michael Girardi
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
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18
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Guenova E, Ødum N. Old Sins Cast Long Shadows: News on Staphylococcus aureus in Cutaneous T Cell Lymphoma. J Invest Dermatol 2024; 144:8-10. [PMID: 37978983 DOI: 10.1016/j.jid.2023.08.031] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 11/19/2023]
Affiliation(s)
- Emmanuella Guenova
- University Hospital Lausanne and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
| | - Niels Ødum
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
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19
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Latzka J, Assaf C, Bagot M, Cozzio A, Dummer R, Guenova E, Gniadecki R, Hodak E, Jonak C, Klemke CD, Knobler R, Morrris S, Nicolay JP, Ortiz-Romero PL, Papadavid E, Pimpinelli N, Quaglino P, Ranki A, Scarisbrick J, Stadler R, Väkevä L, Vermeer MH, Wehkamp U, Whittaker S, Willemze R, Trautinger F. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023. Eur J Cancer 2023; 195:113343. [PMID: 37890355 DOI: 10.1016/j.ejca.2023.113343] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/28/2023] [Accepted: 08/23/2023] [Indexed: 10/29/2023]
Abstract
On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS.
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Affiliation(s)
- Johanna Latzka
- Department of Dermatology and Venereology, University Hospital of St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria; Karl Landsteiner Institute of Dermatological Research, Department of Dermatology and Venereology, University Hospital of St. Pölten, St. Pölten, Austria.
| | - Chalid Assaf
- Department of Dermatology, HELIOS Klinikum Krefeld, Krefeld, Germany; Institute for Molecular Medicine, Medical School Hamburg, University of Applied Sciences and Medical University, Hamburg, Germany; Department of Dermatology, HELIOS Klinikum Schwerin, University Campus of The Medical School Hamburg, Schwerin, Germany
| | - Martine Bagot
- Department of Dermatology, Hopital Saint Louis, Université Paris Cité, INSERM U976, Paris, France
| | - Antonio Cozzio
- Department of Dermatology and Allergology, Kantonspital St. Gallen, St. Gallen, Switzerland
| | - Reinhard Dummer
- Department of Dermatology, University of Zurich, Zurich, Switzerland
| | - Emmanuella Guenova
- Department of Dermatology, University Hospital of Lausanne and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Robert Gniadecki
- Department of Dermatology, University of Copenhagen, Copenhagen, Denmark; Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Emmilia Hodak
- Cutaneous Lymphoma Unit, Davidoff Cancer Center, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Constanze Jonak
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | | | - Robert Knobler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Stephen Morrris
- Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK
| | - Jan P Nicolay
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Mannheim, Germany
| | - Pablo L Ortiz-Romero
- Department of Dermatology, Hospital Universitario 12 de Octubre, Institute i+12, CIBERONC, Medical School, University Complutense, Madrid, Spain
| | - Evangelia Papadavid
- National and Kapodistrian University of Athens, 2nd Department of Dermatology and Venereology, Attikon General Hospital, University of Athens, Chaidari, Greece
| | - Nicola Pimpinelli
- Department of Health Sciences, Division of Dermatology, University of Florence, Florence, Italy
| | - Pietro Quaglino
- Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy
| | - Annamari Ranki
- Department of Dermatology and Allergology, Inflammation Center, Helsinki University Central Hospital, Helsinki, Finland
| | - Julia Scarisbrick
- Department of Dermatology, University Hospital Birmingham, Birmingham, UK
| | - Rudolf Stadler
- University Department of Dermatology, Venereology, Allergology and Phlebology, Skin Cancer Center, Johannes Wesling Medical Centre Minden, Ruhr University Bochum, Bochum, Germany
| | - Liisa Väkevä
- Department of Dermatology and Allergology, Inflammation Center, Helsinki University Central Hospital, Helsinki, Finland
| | - Maarten H Vermeer
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Ulrike Wehkamp
- Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Medical Department, Medical School of Hamburg, Hamburg, Germany
| | - Sean Whittaker
- St. John's Institute of Dermatology, School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Rein Willemze
- Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Franz Trautinger
- Department of Dermatology and Venereology, University Hospital of St. Pölten, Karl Landsteiner University of Health Sciences, St. Pölten, Austria; Karl Landsteiner Institute of Dermatological Research, Department of Dermatology and Venereology, University Hospital of St. Pölten, St. Pölten, Austria
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20
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Savoia P, Azzimonti B, Rolla R, Zavattaro E. Role of the Microbiota in Skin Neoplasms: New Therapeutic Horizons. Microorganisms 2023; 11:2386. [PMID: 37894044 PMCID: PMC10608979 DOI: 10.3390/microorganisms11102386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
The skin and the gut are regularly colonized by a variety of microorganisms capable of interacting with the immune system through their metabolites and influencing the balance between immune tolerance and inflammation. Alterations in the composition and diversity of the skin microbiota have been described in various cutaneous diseases, including skin cancer, and the actual function of the human microbiota in skin carcinogenesis, such as in progression and metastasis, is currently an active area of research. The role of Human Papilloma Virus (HPV) in the pathogenesis of squamous cell carcinoma is well consolidated, especially in chronically immunosuppressed patients. Furthermore, an imbalance between Staphylococcus spp., such as Staphylococcus epidermidis and aureus, has been found to be strongly related to the progression from actinic keratosis to squamous cell carcinoma and differently associated with various stages of the diseases in cutaneous T-cell lymphoma patients. Also, in melanoma patients, differences in microbiota have been related to dissimilar disease course and prognosis and may affect the effectiveness and tolerability of immune checkpoint inhibitors, which currently represent one of the best chances of a cure. From this point of view, acting on microbiota can be considered a possible therapeutic option for patients with advanced skin cancers, even if several issues are still open.
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Affiliation(s)
- Paola Savoia
- Department of Health Science, University of Eastern Piedmont, via Solaroli 17, 28100 Novara, Italy; (B.A.); (R.R.); (E.Z.)
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21
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Pallesen EMH, Gluud M, Vadivel CK, Buus TB, de Rooij B, Zeng Z, Ahmad S, Willerslev-Olsen A, Röhrig C, Kamstrup MR, Bay L, Lindahl L, Krejsgaard T, Geisler C, Bonefeld CM, Iversen L, Woetmann A, Koralov SB, Bjarnsholt T, Frieling J, Schmelcher M, Ødum N. Endolysin Inhibits Skin Colonization by Patient-Derived Staphylococcus Aureus and Malignant T-Cell Activation in Cutaneous T-Cell Lymphoma. J Invest Dermatol 2023; 143:1757-1768.e3. [PMID: 36889662 DOI: 10.1016/j.jid.2023.01.039] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 12/15/2022] [Accepted: 01/10/2023] [Indexed: 03/08/2023]
Abstract
Staphylococcus aureus is suspected to fuel disease activity in cutaneous T-cell lymphomas. In this study, we investigate the effect of a recombinant, antibacterial protein, endolysin (XZ.700), on S. aureus skin colonization and malignant T-cell activation. We show that endolysin strongly inhibits the proliferation of S. aureus isolated from cutaneous T-cell lymphoma skin and significantly decreases S. aureus bacterial cell counts in a dose-dependent manner. Likewise, ex vivo colonization of both healthy and lesional skin by S. aureus is profoundly inhibited by endolysin. Moreover, endolysin inhibits the patient-derived S. aureus induction of IFNγ and the IFNγ-inducible chemokine CXCL10 in healthy skin. Whereas patient-derived S. aureus stimulates activation and proliferation of malignant T cells in vitro through an indirect mechanism involving nonmalignant T cells, endolysin strongly inhibits the effects of S. aureus on activation (reduced CD25 and signal transducer and activator of transcription 5 phosphorylation) and proliferation (reduced Ki-67) of malignant T cells and cell lines in the presence of nonmalignant T cells. Taken together, we provide evidence that endolysin XZ.700 inhibits skin colonization, chemokine expression, and proliferation of pathogenic S. aureus and blocks their potential tumor-promoting effects on malignant T cells.
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Affiliation(s)
- Emil M H Pallesen
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Maria Gluud
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Chella Krishna Vadivel
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Terkild B Buus
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Bob de Rooij
- Micreos Human Health B.V., Bilthoven, the Netherlands
| | - Ziao Zeng
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Sana Ahmad
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Andreas Willerslev-Olsen
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | | | - Maria R Kamstrup
- Department of Dermatology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Lene Bay
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Lise Lindahl
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Thorbjørn Krejsgaard
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Geisler
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M Bonefeld
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Lars Iversen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Anders Woetmann
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Sergei B Koralov
- Department of Pathology, NYU School of Medicine, New York, New York, USA
| | - Thomas Bjarnsholt
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Niels Ødum
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
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22
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Turk S, Yanpar H, Baesmat AS, Canli SD, Cinar OE, Malkan UY, Turk C, Haznedaroglu IC, Ucar G. Enterotoxins A and B produced by Staphylococcus aureus increase cell proliferation, invasion and cytarabine resistance in acute myeloid leukemia cell lines. Heliyon 2023; 9:e19743. [PMID: 37810000 PMCID: PMC10559070 DOI: 10.1016/j.heliyon.2023.e19743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 08/25/2023] [Accepted: 08/31/2023] [Indexed: 10/10/2023] Open
Abstract
As in the case of cancer, the risk of infection increases when the host's immune system is not working properly. It has been shown that toxins produced by the bacteria responsible for bacterial infections can alter the properties of cancer cells as well as their sensitivity to chemotherapy agents. Staphylococcus aureus (S. aureus) is one of the most prevalent pathogens in acute myeloid leukemia (AML) patients and it produces several virulence factors, including Staphylococcal enterotoxin A (SEA) and Staphylococcal enterotoxin B (SEB). Cytotoxicity, transwell migration, invasion assays, and various transcriptomic and gene set enrichment (GSE) analyses were used to determine how SEA and SEB alter cell proliferation, migration, invasion, and Cytarabine (Cyt) resistance in AML cell lines. The treatment of AML cell lines with SEA/SEB caused an increase in cell proliferation and Cyt resistance. Toxins enhanced the proclivity of cells to migrate and invade, with around 50% of cells in the presence of SEA and SEB. Transcriptomic and gene set enrichment analyses, and subsequent PCR validations showed dysregulation of immune related genes and genesets. Apparently, this allows AML cells to escape and survive the undesirable environment created by toxins, possibly via the ER stress signaling pathway. Therefore, SEA and SEB can significantly alter the characteristics of AML cancer cells and evaluation of alterations in responsible immune genes and pathways may be crucial for controlling the progression of cancer. In addition, our results suggest that there may be a strong interaction between the immune related pathways and the ER signaling pathway.
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Affiliation(s)
- Seyhan Turk
- Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
| | - Hatice Yanpar
- DS Nano and Biotechnology Product Tracing and Tracking Co., Ankara, Turkey
| | - Ayriana Safari Baesmat
- Department of Medical Microbiology, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey
| | - Secil Demirkol Canli
- Molecular Pathology Application and Research Center, Hacettepe University, Ankara, Turkey
- Tumor Pathology, Cancer Institute, Hacettepe University, Ankara, Turkey
| | - Olgu Erkin Cinar
- Department of Hematology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Umit Yavuz Malkan
- Department of Hematology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Can Turk
- Department of Medical Microbiology, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey
| | | | - Gulberk Ucar
- Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey
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23
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Deng T, Zheng H, Zhu Y, Liu M, He G, Li Y, Liu Y, Wu J, Cheng H. Emerging Trends and Focus in Human Skin Microbiome Over the Last Decade: A Bibliometric Analysis and Literature Review. Clin Cosmet Investig Dermatol 2023; 16:2153-2173. [PMID: 37583484 PMCID: PMC10424697 DOI: 10.2147/ccid.s420386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/29/2023] [Indexed: 08/17/2023]
Abstract
Background Human skin microbiome is the first barrier against exogenous attack and is associated with various skin disease pathogenesis and progression. Advancements in high-throughput sequencing technologies have paved the way for a deeper understanding of this field. Based on the bibliometric analysis, this investigation aimed to identify the hotspots and future research trends associated with human skin microbiomes studied over the past decade. Methods The published research on skin microbiome from January 2013 to January 2023 was retrieved from the Web of Science Core Collection. Data cleaning processes to ensure robust data and the bibliometrix packages R, CiteSpace, VOSviewer, Origin, and Scimago Graphica for bibliometric and visual analyses were utilized. Results A total of 1629 published documents were analyzed. The overall publication trend steadily increased, with relatively fast growth in 2017 and 2020. The United States of America has the highest number of publications and citations and shows close collaborations with China and Germany. The University of California, San Diego, indicated a higher number of publications than other institutions and the fastest growth rate. The top three most publishing journals on this topic are Microorganisms, Frontiers in Microbiology, and Experimental dermatology. Gallo RL is the most influential author with the highest h- and g-index and most publications in skin microecology, followed by Grice EA and Kong HH. The top 10 most frequently used keywords in recent years included skin microbiome, microbiome, staphylococcus aureus, diversity, atopic dermatitis, skin, bacteria, infections, gut microbiota, and disease. Conclusion The skin microbiome is an area of research that requires continuous analysis, and even with much-achieved progress, future research will further be aided as technology develops.
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Affiliation(s)
- Tinghan Deng
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610075, People’s Republic of China
| | - Huilan Zheng
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610075, People’s Republic of China
| | - Ying Zhu
- Department of Gynecology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610075, People’s Republic of China
| | - Ming Liu
- Department of Medical Oncology/Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China
| | - Guanjin He
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610075, People’s Republic of China
| | - Ya Li
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610075, People’s Republic of China
| | - Yichen Liu
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610075, People’s Republic of China
| | - Jingping Wu
- Department of Medical Cosmetology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610075, People’s Republic of China
| | - Hongbin Cheng
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, 610075, People’s Republic of China
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24
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Di Raimondo C, Lombardo P, Tesei C, Esposito F, Meconi F, Secchi R, Lozzi F, Monopoli A, Narducci MG, Scala E, Angeloni C, De Stefano A, Rahimi S, Bianchi L, Cantonetti M. Role of Neutrophil-to-Lymphocyte Ratio (NLR) in Patients with Mycosis Fungoides. Diagnostics (Basel) 2023; 13:diagnostics13111979. [PMID: 37296831 DOI: 10.3390/diagnostics13111979] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/28/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND The neutrophil/lymphocyte ratio (NLR) at baseline has been demonstrated to correlate with higher stages of disease and to be a prognostic factor in numerous cancers. However, its function as a prognostic factor for mycosis fungoides (MF) has not been yet clarified. OBJECTIVE Our work aimed to assess the association of the NLR with different stages of MF and to outline whether higher values of this marker are related to a more aggressive MF. METHODS We retrospectively calculated the NLRs in 302 MF patients at the moment of diagnosis. The NLR was obtained using the complete blood count values. RESULTS The median NLR among patients with early stage disease (low-grade IA-IB-IIA) was 1.88, while the median NLR for patients with high-grade MF (IIB-IIIA-IIIB) was 2.64. Statistical analysis showed positive associations of advanced MF stages with NLRs higher than 2.3. CONCLUSIONS Our analysis demonstrates that the NLR represents a cheap and easily available parameter functioning as a marker for advanced MF. This might guide physicians in recognizing patients with advanced stages of disease requiring a strict follow-up or an early treatment.
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Affiliation(s)
- Cosimo Di Raimondo
- Department of Dermatology, University of Roma Tor Vergata, 00133 Rome, Italy
| | - Paolo Lombardo
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, 00167 Rome, Italy
| | - Cristiano Tesei
- Department of Hematology, University of Roma Tor Vergata, 00133 Rome, Italy
| | - Fabiana Esposito
- Department of Hematology, University of Roma Tor Vergata, 00133 Rome, Italy
| | - Federico Meconi
- Department of Hematology, University of Roma Tor Vergata, 00133 Rome, Italy
| | - Roberto Secchi
- Department of Hematology, University of Roma Tor Vergata, 00133 Rome, Italy
| | - Flavia Lozzi
- Department of Dermatology, University of Roma Tor Vergata, 00133 Rome, Italy
| | | | | | - Enrico Scala
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, 00167 Rome, Italy
| | - Cecilia Angeloni
- Department of Diagnostic Imaging and Interventional Radiology, University of Roma Tor Vergata, 00133 Rome, Italy
| | - Alberto De Stefano
- Volunteers Association of Fondazione Policlinico "Tor Vergata", 00133 Rome, Italy
| | - Siavash Rahimi
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, 00167 Rome, Italy
| | - Luca Bianchi
- Department of Dermatology, University of Roma Tor Vergata, 00133 Rome, Italy
| | - Maria Cantonetti
- Istituto Dermopatico dell'Immacolata, IDI-IRCCS, 00167 Rome, Italy
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Allen PB, Goyal S, Switchenko J, Tarabadkar E, Pouch S, Parikh P, Palmer A, Martini D, Kim E, Lechowicz MJ. Mitigation strategies among cutaneous T-cell lymphoma patients with positive Staphylococcus aureus skin and soft tissue cultures have unclear impacts on the risk of subsequent bacteremia. Leuk Lymphoma 2023; 64:597-604. [PMID: 35673767 PMCID: PMC9812029 DOI: 10.1080/10428194.2022.2081324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/05/2022] [Accepted: 05/14/2022] [Indexed: 01/07/2023]
Abstract
Infections originating in the skin/soft tissue are a major cause of mortality in cutaneous T-cell lymphoma (CTCL). We performed a retrospective analysis to characterize cutaneous cultures and assess risk factors for bacteremia among 69 patients with CTCL. Cutaneous infections and antimicrobial resistance were common. Black race and lymph node involvement were associated with bacteremia. Mitigating strategies for invasive infections in CTCL remain unclear. HighlightsSkin/soft tissue infections are common in cutaneous T-cell lymphoma (CTCL).Black race, lymph node involvement, and positive cultures for S. aureus, Gram-negative bacteria, or multiple organisms were associated with an increased rate of bacteremia.The role of antimicrobial prophylaxis and staphylococcus decolonization is unclear.
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Affiliation(s)
- Pamela B. Allen
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Subir Goyal
- Department of Biostatistics & Bioinformatics, Rollins School of Public Heath, Emory University
| | - Jeffrey Switchenko
- Department of Biostatistics & Bioinformatics, Rollins School of Public Heath, Emory University
| | - Erica Tarabadkar
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
- Department of Dermatology, Emory University, Atlanta, GA
| | - Stephanie Pouch
- Department of Internal Medicine, Infectious Disease, Emory University, Atlanta, GA
| | - Priya Parikh
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Alex Palmer
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | | | - Esther Kim
- Department of Biostatistics & Bioinformatics, Rollins School of Public Heath, Emory University
- University of Georgia, Athens, GA
| | - Mary Jo Lechowicz
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
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Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma. Blood 2023; 141:180-193. [PMID: 36122387 DOI: 10.1182/blood.2022016690] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 09/01/2022] [Accepted: 09/07/2022] [Indexed: 01/17/2023] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA-mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.
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27
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Hooper MJ, LeWitt TM, Veon FL, Pang Y, Chlipala GE, Feferman L, Green SJ, Sweeney D, Bagnowski KT, Burns MB, Seed PC, Guitart J, Zhou XA. Nasal Dysbiosis in Cutaneous T-Cell Lymphoma Is Characterized by Shifts in Relative Abundances of Non- Staphylococcus Bacteria. JID INNOVATIONS 2022; 2:100132. [PMID: 36161104 PMCID: PMC9500465 DOI: 10.1016/j.xjidi.2022.100132] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 12/26/2022] Open
Abstract
The nasal microbiome of patients with cutaneous T-cell lymphoma (CTCL) remains unexplored despite growing evidence connecting nasal bacteria to skin health and disease. Nasal swabs from 45 patients with CTCL (40 with mycosis fungoides, 5 with Sézary syndrome) and 20 healthy controls from the same geographical region (Chicago Metropolitan Area, Chicago, IL) were analyzed using sequencing of 16S ribosomal RNA and tuf2 gene amplicons. Nasal α-diversity did not differ between mycosis fungoides/Sézary syndrome and healthy controls (Shannon index, genus level, P = 0.201), but distinct microbial communities were identified at the class (R2 = 0.104, P = 0.023) and order (R2 = 0.0904, P = 0.038) levels. Increased relative abundance of the genera Catenococcus, Vibrio, Roseomonas, Acinetobacter, and unclassified Clostridiales was associated with increased skin disease burden (P < 0.005, q < 0.05). Performed to accurately resolve nasal Staphylococcus at the species level, tuf2 gene amplicon sequencing revealed no significant differences between mycosis fungoides/Sézary syndrome and healthy controls. Although S. aureus has been shown to worsen CTCL through its toxins, no increase in the relative abundance of this taxon was observed in nasal samples. Despite the lack of differences in Staphylococcus, the CTCL nasal microbiome was characterized by shifts in numerous other bacterial taxa. These data add to our understanding of the greater CTCL microbiome and provide context for comprehending nasal-skin and host‒tumor‒microbial relationships.
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Affiliation(s)
- Madeline J. Hooper
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Tessa M. LeWitt
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Francesca L. Veon
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Yanzhen Pang
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - George E. Chlipala
- Research Informatics Core, Research Resources Center, University of Illinois Chicago, Chicago, Illinois, USA
| | - Leo Feferman
- Research Informatics Core, Research Resources Center, University of Illinois Chicago, Chicago, Illinois, USA
| | - Stefan J. Green
- Rush Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, Illinois, USA
| | - Dagmar Sweeney
- Genome Research Core, Genome Research Division, Research Resources Center, University of Illinois Chicago, Chicago, Illinois, USA
| | - Katherine T. Bagnowski
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Michael B. Burns
- Department of Biology, Loyola University Chicago, Chicago, Illinois, USA
| | - Patrick C. Seed
- Division of Pediatric Infectious Diseases, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
| | - Joan Guitart
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Xiaolong A. Zhou
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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28
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The Skin Microbiome in Cutaneous T-Cell Lymphomas (CTCL)—A Narrative Review. Pathogens 2022; 11:pathogens11080935. [PMID: 36015055 PMCID: PMC9414712 DOI: 10.3390/pathogens11080935] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 12/02/2022] Open
Abstract
In recent years, numerous studies have shown a significant role of the skin microbiome in the development and exacerbation of skin diseases. Cutaneous T-cell lymphomas (CTCL) are a group of malignancies primary involving skin, with unclear pathogenesis and etiology. As external triggers appear to contribute to chronic skin inflammation and the malignant transformation of T-cells, some microorganisms or dysbiosis may be involved in these processes. Recently, studies analyzing the skin microbiome composition and diversity have been willingly conducted in CTCL patients. In this review, we summarize currently available data on the skin microbiome in CTLC. We refer to a healthy skin microbiome and the contribution of microorganisms in the pathogenesis and progression of other skin diseases, focusing on atopic dermatitis and its similarities to CTCL. Moreover, we present information about the possible role of identified microorganisms in CTCL development and progression. Additionally, we summarize information about the involvement of Staphylococcus aureus in CTCL pathogenesis. This article also presents therapeutic options used in CTCL and discusses how they may influence the microbiome.
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29
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Exploring the Role of Staphylococcus aureus in Inflammatory Diseases. Toxins (Basel) 2022; 14:toxins14070464. [PMID: 35878202 PMCID: PMC9318596 DOI: 10.3390/toxins14070464] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/23/2022] [Accepted: 07/01/2022] [Indexed: 02/04/2023] Open
Abstract
Staphylococcus aureus is a very common Gram-positive bacterium, and S. aureus infections play an extremely important role in a variety of diseases. This paper describes the types of virulence factors involved, the inflammatory cells activated, the process of host cell death, and the associated diseases caused by S. aureus. S. aureus can secrete a variety of enterotoxins and other toxins to trigger inflammatory responses and activate inflammatory cells, such as keratinocytes, helper T cells, innate lymphoid cells, macrophages, dendritic cells, mast cells, neutrophils, eosinophils, and basophils. Activated inflammatory cells can express various cytokines and induce an inflammatory response. S. aureus can also induce host cell death through pyroptosis, apoptosis, necroptosis, autophagy, etc. This article discusses S. aureus and MRSA (methicillin-resistant S. aureus) in atopic dermatitis, psoriasis, pulmonary cystic fibrosis, allergic asthma, food poisoning, sarcoidosis, multiple sclerosis, and osteomyelitis. Summarizing the pathogenic mechanism of Staphylococcus aureus provides a basis for the targeted treatment of Staphylococcus aureus infection.
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Ohadi L, Hosseinzadeh F, Dadkhahfar S, Nasiri S. Oncolytic effect of SARS-CoV-2 in a patient with mycosis fungoides: A case report. Clin Case Rep 2022; 10:e05682. [PMID: 35387287 PMCID: PMC8978791 DOI: 10.1002/ccr3.5682] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/06/2022] [Accepted: 03/15/2022] [Indexed: 12/19/2022] Open
Abstract
The most common variant of cutaneous T-cell lymphomas (CTCL) is mycosis fungoides (MF). Patients with MF often experience a chronic course of disease. The spontaneous regression (SR) of MF is rare, and the factors that predict SR have not been recognized yet. Here, we are reporting a case of persistent MF who had prominent remission after COVID-19. This case report supports the possible antineoplastic effect of SARS-CoV-2. Understanding the underlying etiology of such effect can result in development of new target therapies for MF.
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Affiliation(s)
- Laya Ohadi
- Shahid Beheshti University of Medical SciencesTehranIran
| | | | - Sahar Dadkhahfar
- Skin Research CenterShahid Beheshti Universiry of Medical SciencesTehranIran
| | - Soheila Nasiri
- Skin Research CenterShahid Beheshti Universiry of Medical SciencesTehranIran
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31
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The Skin Microbiome and Influencing Elements in Cutaneous T-Cell Lymphomas. Cancers (Basel) 2022; 14:cancers14051324. [PMID: 35267632 PMCID: PMC8909499 DOI: 10.3390/cancers14051324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/18/2022] [Accepted: 03/01/2022] [Indexed: 12/29/2022] Open
Abstract
Simple Summary Since the 1970s, a connection between microbes living on the skin and the rare cutaneous neoplasia, cutaneous T-cell lymphomas (CTCL), was suggested. New technologies, for instance, next-generation sequencing technologies, enable investigators to look closely at the interplay between microbes and the host. In the present review, we collected research regarding the role of skin microbiota and skin barrier elements in the most common CTCL. It is known that Staphylococcus aureus infections play a major role in morbidity and mortality in advanced stages of the disease. It is possible that the microbiota of the patient might be involved in disease progression or its origin. Some findings suggest that the skin barrier may be deficient in CTCL. Restoring the skin barrier in CTCL might be a promising therapeutical option. Further studies are needed to provide more insight and potentially contribute to the development of new treatment approaches. Abstract Since the 1970s, a connection between the skin’s microbiota and cutaneous T-cell lymphomas (CTCL) was suggested. New techniques such as next-generation sequencing technologies enable the examination of the nuanced interplay between microbes and their host. The purpose of this review is an updated description of the current knowledge on the composition of the microbiome, relevant bacteria, or other stimuli, and their potential role in CTCL with a focus on the most frequent subtype, mycosis fungoides. Some findings suggest that the skin barrier—or the deficiency hereof—and host-microbiota might be involved in disease progression or etiopathogenesis. In addition, information on the current knowledge of antimicrobial peptide expression in CTCL, as well as treatment considerations with antiseptics and antibiotics, are included. Further studies are needed to provide more insight and potentially contribute to the development of new treatment approaches.
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Licht P, Mailänder V. Transcriptional Heterogeneity and the Microbiome of Cutaneous T-Cell Lymphoma. Cells 2022; 11:cells11030328. [PMID: 35159138 PMCID: PMC8834405 DOI: 10.3390/cells11030328] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 12/31/2021] [Accepted: 01/13/2022] [Indexed: 11/16/2022] Open
Abstract
Cutaneous T-Cell Lymphomas (CTCL) presents with substantial clinical variability and transcriptional heterogeneity. In the recent years, several studies paved the way to elucidate aetiology and pathogenesis of CTCL using sequencing methods. Several T-cell subtypes were suggested as the source of disease thereby explaining clinical and transcriptional heterogeneity of CTCL entities. Several differentially expressed pathways could explain disease progression. However, exogenous triggers in the skin microenvironment also seem to affect CTCL status. Especially Staphylococcus aureus was shown to contribute to disease progression. Only little is known about the complex microbiome patterns involved in CTCL and how microbial shifts might impact this malignancy. Nevertheless, first hints indicate that the microbiome might at least in part explain transcriptional heterogeneity and that microbial approaches could serve in diagnosis and prognosis. Shaping the microbiome could be a treatment option to maintain stable disease. Here, we review current knowledge of transcriptional heterogeneity of and microbial influences on CTCL. We discuss potential benefits of microbial applications and microbial directed therapies to aid patients with CTCL burden.
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Affiliation(s)
- Philipp Licht
- Dermatology Clinic, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany;
| | - Volker Mailänder
- Dermatology Clinic, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany;
- Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
- Correspondence:
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The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome. Int J Mol Sci 2022; 23:ijms23020936. [PMID: 35055124 PMCID: PMC8781892 DOI: 10.3390/ijms23020936] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/11/2021] [Accepted: 12/19/2021] [Indexed: 02/05/2023] Open
Abstract
Sézary syndrome is an aggressive leukemic variant of cutaneous T-cell lymphomas, characterized by erythroderma, lymphadenopathy, and peripheral blood involvement by CD4+ malignant T-cells. The pathogenesis of Sézary syndrome is not fully understood. However, the course of the disease is strongly influenced by the tumor microenvironment, which is altered by a combination of cytokines, chemokines, and growth factors. The crosstalk between malignant and reactive cells affects the immunologic response against tumor cells causing immune dysregulation. This review focuses on the interaction of malignant Sézary cells and the tumor microenvironment.
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Wen P, Xie Y, Wang L. The Role of microRNA in Pathogenesis, Diagnosis, Different Variants, Treatment and Prognosis of Mycosis Fungoides. Front Oncol 2021; 11:752817. [PMID: 34966672 PMCID: PMC8710607 DOI: 10.3389/fonc.2021.752817] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 11/12/2021] [Indexed: 02/05/2023] Open
Abstract
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), accounting for approximately 50% of all CTCLs. Although various molecular changes in MF have been described in existing studies, no obvious disease-specific changes have been found thus far. microRNAs (miRs) are short, noncoding RNA molecules that play roles in the post-transcriptional regulation of oncogenes and tumor suppressor genes in various diseases. Recently, there has been rapidly expanding experimental evidence for the role of miRs in the progression, early diagnosis, prognosis prediction for MF. Efforts to improve early diagnosis and develop personalized therapy options have become more important in recent years. Here, we provide an overview and update of recent advances regarding miRs associated with MF. Furthermore, we provide insights into future opportunities for miR-based therapies.
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Affiliation(s)
- Pengfei Wen
- Department of Dermatovenerology, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Xie
- Department of Dermatovenerology, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Wang
- Department of Dermatovenerology, West China Hospital, Sichuan University, Chengdu, China
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Fujii K. Pathogenesis of cutaneous T cell lymphoma: Involvement of Staphylococcus aureus. J Dermatol 2021; 49:202-209. [PMID: 34927279 DOI: 10.1111/1346-8138.16288] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/11/2021] [Accepted: 12/13/2021] [Indexed: 12/30/2022]
Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) are representative cutaneous lymphomas. In their early stage, a small number of tumor cells and a large number of non-malignant cells form a Th1-dominant tumor microenvironment. Increase in malignant T cells is accompanied by a decrease in CD8-positive T cells, with a shift toward a Th2-dominant milieu in advanced-stage lesions. The etiologies of MF/SS are diverse, and the underlying pathogenetic mechanisms are yet to be elucidated. Advanced MF/SS is known to be highly sensitive to Staphylococcus aureus, and the majority of deaths are caused by severe infections. The susceptibility to infection is associated with barrier dysfunction and immunosuppression, which are the main symptoms of MF. In recent years, skin-colonizing S. aureus has been identified to not only cause severe infections but also play an important role in the pathogenesis of MF/SS. Staphylococcal superantigens activate the proliferation of tumor cells and induce CD25 upregulation, FOXP3 expression, IL-17 expression, and miR-155 expression. Alpha-toxin eliminates non-neoplastic CD4-positive cells and CD8-positive cells and plays a major role in tumor cell selection. Lipoprotein may also be associated with the induction of Th2-dominant milieu. Antibiotic therapy for S. aureus eradication has been reported to cause considerable clinical improvement in the majority of individuals with advanced cutaneous T-cell lymphoma. Therefore, S. aureus may be a novel target for the treatment of advanced-stage MF/SS in the future.
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Affiliation(s)
- Kazuyasu Fujii
- Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Lindahl LM, Iversen L, Ødum N, Kilian M. Staphylococcus aureus and Antibiotics in Cutaneous T-Cell Lymphoma. Dermatology 2021; 238:551-553. [PMID: 34619677 DOI: 10.1159/000517829] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/05/2021] [Indexed: 11/19/2022] Open
Affiliation(s)
- Lise M Lindahl
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark,
| | - Lars Iversen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Ødum
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Mogens Kilian
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
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IL-31 and IL-8 in Cutaneous T-Cell Lymphoma: Looking for Their Role in Itch. Adv Hematol 2021; 2021:5582581. [PMID: 34335777 PMCID: PMC8318769 DOI: 10.1155/2021/5582581] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 06/21/2021] [Accepted: 07/13/2021] [Indexed: 01/26/2023] Open
Abstract
The itch associated with cutaneous T-cell lymphoma (CTCL), including Mycosis Fungoides (MF) and Sézary syndrome (SS), is often severe and poorly responsive to treatment with antihistamines. Recent studies have highlighted the possible role of interleukins in nonhistaminergic itch. We investigated the role of IL-31 and IL-8 in CTCL, concerning disease severity and associated itch. Serum samples of 27 patients with CTCL (17 MF and 10 SS) and 29 controls (blood donors) were analyzed for interleukin- (IL-) 31 and IL-8; correlations with disease and itch severity were evaluated. IL-31 serum levels were higher in CTCL patients than in controls and higher in SS than in MF. Also, serum IL-31 levels were higher in patients with advanced disease compared to those with early disease, and they correlated positively with lactate dehydrogenase and beta 2-microglobulin levels, as well as with the Sézary cell count. Itch affected 67% of CTCL patients (MF: 47%; SS: 100%). Serum IL-31 levels were higher in itching patients than in controls and in patients without itching. There was no association between serum IL-8 and disease severity, nor with itching. Serum IL-8 levels correlated positively with peripheral blood leukocyte and neutrophil counts in CTCL patients. Our study suggests a role for IL-31 in CTCL-associated itch, especially in advanced disease and SS, offering a rational target for new therapeutic approaches. Increased serum IL-8 observed in some patients may be related to concomitant infections, and its role in exacerbating itch by recruiting neutrophils and promoting the release of neutrophil proteases deserves further investigation.
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Pavlidis A, Piperi C, Papadavid E. Novel therapeutic approaches for cutaneous T cell lymphomas. Expert Rev Clin Immunol 2021; 17:629-641. [PMID: 33890833 DOI: 10.1080/1744666x.2021.1919085] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin's lymphoma, characterized by malignant T cells infiltrating the skin. CTCL exhibits vast heterogeneity which complicates diagnosis and therapeutic strategies. Current CTCL treatment includes skin-directed therapies (such as topical corticosteroid, topical mechlorethamine, topical bexarotene, ultraviolet phototherapy and localized radiotherapy), total skin electron beam therapy and systemic therapies. Elucidation of molecular and signaling pathways underlying CTCL pathogenesis leads to identification of innovative and personalized treatment schemes.Areas covered: The authors reviewed the molecular and immunological aspects of CTCL with special focus on Mycosis Fungoides (MF), Sézary Syndrome (SS) and associated systemic treatment. A literature search was conducted in PubMed and Web of Science for peer-reviewed articles published until November 2020. Novel treatment approaches including retinoids, targeted therapies, immune checkpoint and JAK/STAT inhibitors, histones deacetylase (HDAC) and mTOR inhibitors as well as proteasome inhibitors, are discussed as potential therapeutic tools for the treatment of CTCL.Expert opinion: Novel therapeutic agents exhibit potential beneficial effects in CTCL patients of high need for therapy such as refractory early stage cutaneous and advanced stage disease. Therapeutic schemes employing a combination of novel agents with current treatment options may prove valuable for the future management of CTCL patients.
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Affiliation(s)
- Antreas Pavlidis
- 2nd Department of Dermatology and Venereal Diseases, Attikon General University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelia Papadavid
- 2nd Department of Dermatology and Venereal Diseases, Attikon General University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Willerslev-Olsen A, Gjerdrum LMR, Lindahl LM, Buus TB, Pallesen EMH, Gluud M, Bzorek M, Nielsen BS, Kamstrup MR, Rittig AH, Bonefeld CM, Krejsgaard T, Geisler C, Koralov SB, Litman T, Becker JC, Woetmann A, Iversen L, Odum N. Staphylococcus aureus Induces Signal Transducer and Activator of Transcription 5‒Dependent miR-155 Expression in Cutaneous T-Cell Lymphoma. J Invest Dermatol 2021; 141:2449-2458. [PMID: 33862068 DOI: 10.1016/j.jid.2021.01.038] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 12/26/2022]
Abstract
Staphylococcal enterotoxins are believed to fuel disease activity in cutaneous T-cell lymphoma. Recent data support this by showing that antibiotics inhibit malignant T cells in skin lesions in mycosis fungoides and Sézary syndrome, the most common forms of cutaneous T-cell lymphoma. Yet, it remains incompletely characterized how staphylococcal enterotoxins fuel disease activity. In this study, we show that staphylococcal enterotoxins induce the expression of the oncogenic microRNA miR-155 in primary malignant T cells. Thus, staphylococcal enterotoxins and Staphyloccocus aureus isolates from lesional skin of patients induce miR-155 expression at least partly through the IL-2Rg‒Jak‒signal transducer and activator of transcription 5 pathway, and the effect is augmented by the presence of nonmalignant T cells. Importantly, mycosis fungoides lesions harbor S. aureus, express Y-phosphorylated signal transducer and activator of transcription 5, and display enhanced miR-155 expression, when compared with nonlesional and healthy skin. Preliminary data show that aggressive antibiotic therapy is associated with decreased Y-phosphorylated signal transducer and activator of transcription 5 and miR-155 expression in lesional skin in two patients with Sézary syndrome. In conclusion, we show that S. aureus and its enterotoxins induce enhanced expression of oncogenic miR-155, providing mechanistic insight into the role of S. aureus in cutaneous T-cell lymphoma. Our findings support that environmental stimuli such as bacteria can fuel disease progression in cutaneous T-cell lymphoma.
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Affiliation(s)
- Andreas Willerslev-Olsen
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Lise Mette Rahbek Gjerdrum
- Department of Pathology, Zealand University Hospital, Roskilde, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Lise M Lindahl
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Terkild B Buus
- 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
| | - Maria Gluud
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Michael Bzorek
- Department of Pathology, Zealand University Hospital, Roskilde, Denmark
| | | | - Maria R Kamstrup
- Department of Dermatology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
| | - Anne Hald Rittig
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Charlotte M Bonefeld
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Thorbjørn Krejsgaard
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Geisler
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Sergei B Koralov
- Department of Pathology, New York University School of Medicine, New York, New York, USA
| | - Thomas Litman
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Jurgen C Becker
- Department of Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital of Essen, Essen, Germany; Deutsches Krebsforschungsinstitut (DKFZ), Heidelberg, Germany
| | - Anders Woetmann
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Lars Iversen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Odum
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
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Mycosis Fungoides and Sézary Syndrome: An Integrative Review of the Pathophysiology, Molecular Drivers, and Targeted Therapy. Cancers (Basel) 2021; 13:cancers13081931. [PMID: 33923722 PMCID: PMC8074086 DOI: 10.3390/cancers13081931] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 12/29/2022] Open
Abstract
Simple Summary In the last few years, the field of cutaneous T-cell lymphomas has experienced major advances. In the context of an active translational and clinical research field, next-generation sequencing data have boosted our understanding of the main molecular mechanisms that govern the biology of these entities, thus enabling the development of novel tools for diagnosis and specific therapy. Here, we focus on mycosis fungoides and Sézary syndrome; we review essential aspects of their pathophysiology, provide a rational mechanistic interpretation of the genomic data, and discuss the current and upcoming therapies, including the potential crosstalk between genomic alterations and the microenvironment, offering opportunities for targeted therapies. Abstract Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.
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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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42
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Reneau JC, Wilcox RA. Novel therapies targeting cutaneous T cell lymphomas and their microenvironment. Semin Hematol 2021; 58:103-113. [PMID: 33906720 DOI: 10.1053/j.seminhematol.2021.02.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/24/2021] [Accepted: 02/01/2021] [Indexed: 01/08/2023]
Abstract
Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas with a generally indolent course managed with topical, skin-directed therapies. A small subset, however, will progress to advanced stage disease necessitating systemic therapy for disease control. Currently approved therapies have low response rates and generally short durations of response. Novel therapies, therefore, are urgently needed to address this unmet need. In this review, the mechanisms of CTCL pathogenesis and progression, including the role of the tumor microenvironment and molecular alterations, are summarized. Based on these biologic insights, novel therapies currently under investigation and those with a strong preclinical biologic rationale including T cell and macrophage checkpoint inhibitors, epigenetic regulators, targeted antibodies, tyrosine kinase inhibitors, and apoptosis modulating therapies are discussed.
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Affiliation(s)
- John C Reneau
- The Ohio State University, Division of Hematology, Columbus, OH.
| | - Ryan A Wilcox
- Division of Hematology/Oncology, University of Michigan Cancer Center, Ann Arbor, MI
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43
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Iżykowska K, Rassek K, Korsak D, Przybylski GK. Novel targeted therapies of T cell lymphomas. J Hematol Oncol 2020; 13:176. [PMID: 33384022 PMCID: PMC7775630 DOI: 10.1186/s13045-020-01006-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 11/22/2020] [Indexed: 02/06/2023] Open
Abstract
T cell lymphomas (TCL) comprise a heterogeneous group of non-Hodgkin lymphomas (NHL) that often present at an advanced stage at the time of diagnosis and that most commonly have an aggressive clinical course. Treatment in the front-line setting is most often cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens, which are effective in B cell lymphomas, but in TCL are associated with a high failure rate and frequent relapses. Furthermore, in contrast to B cell NHL, in which substantial clinical progress has been made with the introduction of monoclonal antibodies, no comparable advances have been seen in TCL. To change this situation and improve the prognosis in TCL, new gene-targeted therapies must be developed. This is now possible due to enormous progress that has been made in the last years in the understanding of the biology and molecular pathogenesis of TCL, which enables the implementation of the research findings in clinical practice. In this review, we present new therapies and current clinical and preclinical trials on targeted treatments for TCL using histone deacetylase inhibitors (HDACi), antibodies, chimeric antigen receptor T cells (CARTs), phosphatidylinositol 3-kinase inhibitors (PI3Ki), anaplastic lymphoma kinase inhibitors (ALKi), and antibiotics, used alone or in combinations. The recent clinical success of ALKi and conjugated anti-CD30 antibody (brentuximab-vedotin) suggests that novel therapies for TCL can significantly improve outcomes when properly targeted.
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Affiliation(s)
- Katarzyna Iżykowska
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479, Poznań, Poland
| | - Karolina Rassek
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479, Poznań, Poland
| | - Dorota Korsak
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479, Poznań, Poland
| | - Grzegorz K Przybylski
- Institute of Human Genetics, Polish Academy of Sciences, Strzeszyńska 32, 60-479, Poznań, Poland.
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Vonderheid EC, Hamilton RG, Kadin ME. Mycosis Fungoides and Its Relationship to Atopy, Serum Total IgE, and Eosinophil Counts. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2020; 21:279-288.e7. [PMID: 33342729 DOI: 10.1016/j.clml.2020.11.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 11/03/2020] [Accepted: 11/07/2020] [Indexed: 01/18/2023]
Abstract
INTRODUCTION A recent serologic study and reports of increased serum total IgE (IgE-t) and eosinophil counts have suggested that the prevalence of atopy is more common in patients with mycosis fungoides (MF) than previously recognized. PATIENTS AND METHODS Patients with clinicopathologic features that were diagnostic and/or consistent with MF and/or the presence or absence of an atopic disorder (eg, allergic rhinitis, asthma, eczematous dermatitis), which was determined by patient history, eosinophil counts, and serum IgE-t obtained at evaluation, were selected from a patient registry. The MF population was divided into those with atypical and typical clinical presentations. We performed matching of controls using age, sex, and race from the 2005 to 2006 National Health Education Survey. RESULTS A history of allergic rhinitis was recorded for 186 of 728 patients (25.5%) with typical MF and 71 of 229 patients (31%) with atypical MF. However, the prevalence of asthma and eczema was low. The IgE-t and eosinophil counts were higher for patients with typical MF than for controls and for patients with atopic diathesis than for patients without atopy. The IgE-t and eosinophil counts were higher for the patients with advanced-stage MF compared with those for the patients with less-advanced disease for both atopic and nonatopic cohorts. In the Cox model with age and clinical stage as covariates, a history of atopy, increased IgE-t, and blood eosinophilia (> 500 cells/mm3) did not correlate with overall survival. CONCLUSION The findings from the present study did not reveal a significant association of atopy in patients with MF. However, atopy is a factor in the increased IgE-t and eosinophil counts observed in MF. Another factor is related to the disease stage, including possibly the influence of cytokines secreted by T-helper type 2-polarized neoplastic cells.
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Affiliation(s)
- Eric C Vonderheid
- Sydney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Tucson, AZ
| | - Robert G Hamilton
- Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Marshall E Kadin
- Department of Dermatology, Boston University and Roger Williams Medical Center; Department of Pathology and Laboratory Medicine, Brown University Alpert Medical School, Providence RI.
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Stolearenco V, Namini MRJ, Hasselager SS, Gluud M, Buus TB, Willerslev-Olsen A, Ødum N, Krejsgaard T. Cellular Interactions and Inflammation in the Pathogenesis of Cutaneous T-Cell Lymphoma. Front Cell Dev Biol 2020; 8:851. [PMID: 33015047 PMCID: PMC7498821 DOI: 10.3389/fcell.2020.00851] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/10/2020] [Indexed: 12/17/2022] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) comprises a group of lymphoproliferative diseases characterized by the accumulation of malignant T cells in chronically inflamed skin lesions. In early stages, the disease presents as skin patches or plaques covering a limited area of the skin and normally follows an indolent course. However, in a subset of patients the cutaneous lesions develop into tumors and the malignant T cells may spread to the lymphatic system, blood and internal organs with fatal consequences. Despite intensive research, the mechanisms driving disease progression remain incompletely understood. While most studies have focused on cancer cell-intrinsic oncogenesis, such as genetic and epigenetic events driving malignant transformation and disease progression, an increasing body of evidence shows that the interplay between malignant T cells and non-malignant cells plays a crucial role. Here, we outline some of the emerging mechanisms by which tumor, stromal and epidermal interactions may contribute to the progression of CTCL with particular emphasis on the crosstalk between fibroblasts, keratinocytes and malignant T cells.
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Affiliation(s)
- Veronica Stolearenco
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Martin R J Namini
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Siri S Hasselager
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Maria Gluud
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Terkild B Buus
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Andreas Willerslev-Olsen
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Niels Ødum
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Thorbjørn Krejsgaard
- LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
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Single-Cell Heterogeneity of Cutaneous T-Cell Lymphomas Revealed Using RNA-Seq Technologies. Cancers (Basel) 2020; 12:cancers12082129. [PMID: 32751918 PMCID: PMC7464763 DOI: 10.3390/cancers12082129] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/16/2020] [Accepted: 07/29/2020] [Indexed: 01/04/2023] Open
Abstract
Cutaneous T-cell lymphomas (CTCLs) represent a large, heterogeneous group of non-Hodgkin lymphomas that primarily affect the skin. Among multiple CTCL variants, the most prevalent types are mycosis fungoides (MF) and Sézary syndrome (SS). In the past decade, the molecular genetics of CTCL have been the target of intense study, increasing the knowledge of CTCL genomic alterations, discovering novel biomarkers, and potential targets for patient-specific therapy. However, the detailed pathogenesis of CTCL development still needs to be discovered. This review aims to summarize the novel insights into molecular heterogeneity of malignant cells using high-throughput technologies, such as RNA sequencing and single-cell RNA sequencing, which might be useful to identify tumour-specific molecular signatures and, therefore, offer guidance for therapy, diagnosis, and prognosis of CTCL.
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Bobrowicz M, Fassnacht C, Ignatova D, Chang YT, Dimitriou F, Guenova E. Pathogenesis and Therapy of Primary Cutaneous T-Cell Lymphoma: Collegium Internationale Allergologicum (CIA) Update 2020. Int Arch Allergy Immunol 2020; 181:733-745. [PMID: 32690848 DOI: 10.1159/000509281] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 05/29/2020] [Indexed: 11/19/2022] Open
Abstract
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous disease group of unknown etiology with a complex immunological background. As CTCL arises from T cells that have a vital role in the antitumor response, their therapy is largely aimed at reversing the immunological mechanisms leading to or manifesting during this malignancy. Early disease stages can be controlled with skin-directed therapy in most CTCL cases. Still, advanced CTCL has a dismal prognosis and warrants systemic therapy. Despite considerable progress in understanding the pathophysiology of the disease and the numerous systemic treatment options available, long-term remission rates with conventional treatments alone are still low. Allogeneic hematopoietic stem cell transplantation is currently the only curative option for advanced CTCL, including mycosis fungoides and Sézary syndrome. The aims of this review is to summarize the recent findings on the immunology of this heterogeneous disease and to present the advances in its clinical management.
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Affiliation(s)
| | - Christina Fassnacht
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Desislava Ignatova
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Yun-Tsan Chang
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland.,Department of Dermatology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.,Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Florentia Dimitriou
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Emmanuella Guenova
- Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland, .,Faculty of Medicine, University of Zurich, Zurich, Switzerland, .,Department of Dermatology, Lausanne University Hospital (CHUV), Lausanne, Switzerland, .,Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland,
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Allen PB, Switchenko J, Ayers A, Kim E, Lechowicz MJ. Risk of bacteremia in patients with cutaneous T-cell lymphoma (CTCL). Leuk Lymphoma 2020; 61:2652-2658. [PMID: 32558600 DOI: 10.1080/10428194.2020.1779259] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Patients with CTCL are at increased risk for bacteremia which is a leading cause of morbidity and mortality. We assessed risk factors for and the impact of bacteremia on survival in a retrospective cohort of 188 CTCL patients at a single US academic institution treated between 1990 and 2018. With a median follow up of 6.2 years, 20% of patients (n = 36) developed 79 bacteremia events. Risk factors for bacteremia included advanced stage, female gender, African American (AA) race, invasive lines, and chemotherapy. Bacteremia was associated with an increased risk of death on univariate and multivariable models. Bacteremia is associated with an increased risk of death in patients with CTCL. The greatest avoidable risk factors included chemotherapy treatment and presence of an invasive line. Key points 20% of patients developed bacteremia at any point in time in this analysis. Bacteremia is associated with an increased risk of death in patients with CTCL Risk factors for bacteremia include advanced stage, female gender, AA race, invasive line, and chemotherapy.
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Affiliation(s)
- Pamela B Allen
- Department of Hematology/Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Jeffrey Switchenko
- Department of Research Informatics, Rollins Scholl of Public Health, Atlanta, GA, USA
| | - Amy Ayers
- Department of Hematology/Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Esther Kim
- Department of Hematology/Oncology Summer Scholar Research Program, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Mary Jo Lechowicz
- Department of Hematology/Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
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Abstract
The majority of patients with Sézary syndrome (SS) present with classic symptoms of erythroderma, lymphadenopathy, and pruritus. However, there have been numerous reports of patients with SS who have non-classic signs. In this review, we report the less common clinical presentations of SS and discuss their relevant treatments. Our search included all literature on SS since 2008, the year the World Health Organization (WHO) incorporated the diagnostic criteria for SS into the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. We reviewed 896 articles and identified 505 patients with non-classic presentations of SS. Of these 505 patients, the most common non-classic signs of SS were keratoderma, onychodystrophy, alopecia, leonine facies, and ectropion. Given the aggressive and highly symptomatic nature of SS, it is imperative that clinicians recognize the less common signs of the disease to prevent delays in diagnosis and treatment. To our knowledge, this is the first review of the clinical variations of SS with a focus on non-classic signs and symptoms.
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Affiliation(s)
- Lisa Morris
- University of Missouri-Columbia School of Medicine, Columbia, MO, USA
| | - Jessica Tran
- Baylor College of Medicine, Houston, TX, USA.
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1452, Houston, TX, 77030, USA.
| | - Madeleine Duvic
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 1452, Houston, TX, 77030, USA
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Phyo ZH, Shanbhag S, Rozati S. Update on Biology of Cutaneous T-Cell Lymphoma. Front Oncol 2020; 10:765. [PMID: 32477957 PMCID: PMC7235328 DOI: 10.3389/fonc.2020.00765] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 04/21/2020] [Indexed: 12/11/2022] Open
Abstract
Cutaneous T cell lymphomas (CTCL) comprise of a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing T cells. Variation in clinical presentation and lack of definitive molecular markers make diagnosis especially challenging. The biology of CTCL remains elusive and clear links between genetic aberrations and epigenetic modifications that would result in clonal T cell expansion have not yet been identified. Nevertheless, in recent years, next generation sequencing (NGS) has enabled a much deeper understanding of the genomic landscape of CTCL by uncovering aberrant genetic pathways and epigenetic dysregulations. Additionally, single cell profiling is rapidly advancing our understanding of patients-specific tumor landscape and its interaction with the surrounding microenvironment. These studies have paved the road for future investigations that will explore the functional relevance of genetic alterations in the progression of disease. The ultimate goal of elucidating the pathogenesis of CTCL is to establish effective therapeutic targets with more durable clinical response and treat relapsing and refractory CTCL.
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Affiliation(s)
- Zaw H Phyo
- Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Satish Shanbhag
- Departments of Oncology and Medicine, Johns Hopkins University, Baltimore, MD, United States
| | - Sima Rozati
- Department of Dermatology, Johns Hopkins University, Baltimore, MD, United States
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