Tumor microenvironment in mycosis fungoides and Sézary syndrome

González, Belén Rubio; Zain, Jasmine; Rosen, Steven T.; Querfeld, Christiane

doi:10.1097/cco.0000000000000243

Cited by 58 publications

(68 citation statements)

References 73 publications

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“…Additionally, there is mounting evidence that the non-tumorous cells and tissues present in the tumor contribute significantly to the pathogenesis of CTCL. Immune evasion, mediated by a variety of immune cells and their cytokine profiles, seems to be critical for the biological behavior of CTCL [4,11]. This review focuses on current strategies to target cellular and molecular components within the CTCL tumor microenvironment, which influence CTCL biology.…”

Section: Introductionmentioning

confidence: 99%

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

et al. 2017

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Cutaneous T-cell lymphomas (CTCL) are a rare and biologically heterogeneous malignant entity comprising mycosis fungoides and Sézary syndrome as the most common subtypes. The current treatment outcome is characterized by high rates of relapse, but survival is usually not significantly shortened in low-stage disease. This is different in tumor-stage disease or aggressive CTCL subtypes where survival is significantly reduced. Recent advances have been made on several levels of tumor biology: Whole genome sequencing has resulted in novel strategies of NF-κB or JAK inhibition, ongoing translational research has revealed new targets like CD30 or CCR4, and, finally, research focusing on impaired immunosurveillance has gained more importance. Based on the growing knowledge about the functional roles of the tumor microenvironment and non-malignant infiltrating cells, current research aims to develop novel CTCL treatment strategies. This review focuses on the mounting evidence for efficiently targeting tumor-infiltrating immune cells and thereby modulating the tumor microenvironment and restoring immunosurveillance.

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Section: Introductionmentioning

confidence: 99%

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

et al. 2017

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“…As expected [53], reads for the miR-21HG promoter were also detected in chromatin precipitated with STAT3 antibody (Figure 2C, upper part, first row) but the number was lower than in STAT5-precipitated chromatin (Figure 2C, upper part, first row). The NFkB pathway is activated in malignant T cells (reviewed in [54] and as RelA and RelB drive pri-miR-21 expression in some cancers like prostate cancer [53], we addressed whether this pathway was also involved. However, only a few reads were detected in chromatin precipitated with RelA and RelB (Figure 2C, middle part), and comparable to what was seen with a control antibody (Figure 2C, lower part).…”

Section: Resultsmentioning

confidence: 99%

STAT5 induces miR-21 expression in cutaneous T cell lymphoma

et al. 2016

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In cutaneous T cell lymphomas (CTCL), miR-21 is aberrantly expressed in skin and peripheral blood and displays anti-apoptotic properties in malignant T cells. It is, however, unclear exactly which cells express miR-21 and what mechanisms regulate miR-21. Here, we demonstrate miR-21 expression in situ in both malignant and reactive lymphocytes as well as stromal cells. qRT-PCR analysis of 47 patients with mycosis fungoides (MF) and Sezary Syndrome (SS) confirmed an increased miR-21 expression that correlated with progressive disease. In cultured malignant T cells miR-21 expression was inhibited by Tofacitinib (CP-690550), a clinical-grade JAK3 inhibitor. Chromatin immunoprecipitation (ChIP) analysis showed direct binding of STAT5 to the miR-21 promoter. Cytokine starvation ex vivo triggered a decrease in miR-21 expression, whereas IL-2 induced an increased miR-21 expression in primary SS T cells and cultured cytokine-dependent SS cells (SeAx). siRNA-mediated depletion of STAT5 inhibited constitutive- and IL-2-induced miR-21 expression in cytokine-independent and dependent T cell lines, respectively. IL-15 and IL-2 were more potent than IL-21 in inducing miR-21 expression in the cytokine-dependent T cells. In conclusion, we provide first evidence that miR-21 is expressed in situ in CTCL skin lesions, induced by IL-2 and IL-15 cytokines, and is regulated by STAT5 in malignant T cells. Thus, our data provide novel evidence for a pathological role of IL-2Rg cytokines in promoting expression of the oncogenic miR-21 in CTCL.

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“…In mouse models, knockdown of Stat5 results in a 40% inhibition of MIR155 expression, supporting the use of MIR155 and JAK/STAT inhibitors as future therapeutic targets for relapsed/refractory CTCL (Kopp et al, 2013;Rubio Gonzalez et al, 2016). Malignant T cells in MF and SS overexpress IL2RA (CD25) that results from a cascade of phosphorylation of several proteins including JAK3, STAT5 and STAT3 (Nielsen et al, 1999;Sommer et al, 2004).…”

Section: Immunological and Molecular Hallmarksmentioning

confidence: 99%

“…Chemokines produced by epidermal and dermal dendritic cells within the tumour microenvironment may also play important roles in attracting malignant T-cell to the skin and several studies have shown a protumourigenic role of mast cells and macrophages. Therefore the malignant T-cells might be functionally exhausted due to continuous antigen overload expressing PD1, LAG3, CTLA4 and ICOS similar to that seen in chronic viral infections suggesting a role for immune checkpoint inhibitor therapies Rubio Gonzalez et al, 2016).…”

Section: Immunological and Molecular Hallmarksmentioning

confidence: 99%

Clinical manifestations and pathogenesis of cutaneous lymphomas: current status and future directions

et al. 2016

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SummaryThe primary cutaneous lymphomas are a heterogeneous group of T-, Natural Killer-and B-cell neoplasms with a wide range of clinical and pathological presentations, and with very different prognoses compared to systemic lymphomas. Recent studies have shown that the skin microenvironment, which is composed of various immune cell subsets as well as their spatial distribution and T-cell interactions through different chemokines and cytokines, has an important role in the development and pathogenesis of cutaneous lymphomas and has assisted in the development of novel and more effective immunotherapies. The following review will focus on the major subtypes of primary cutaneous lymphomas, including the clinical and histological patterns, molecular hallmarks, and current and future treatment strategies.

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Tumor microenvironment in mycosis fungoides and Sézary syndrome

Abstract: All these new findings could assist in the development of novel targeted therapies for CTCL.

Cited by 58 publications

References 73 publications

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

STAT5 induces miR-21 expression in cutaneous T cell lymphoma

Clinical manifestations and pathogenesis of cutaneous lymphomas: current status and future directions

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