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Mycosis Fungoides and Sezary Syndrome: Microenvironment and Cancer Progression.

ABSTRACT: Mycosis fungoides and Sézary syndrome are epidermotropic cutaneous lymphomas, and both of them are rare diseases. Mycosis fungoides is the most frequent primary cutaneous lymphoma. In about 25% of patients with mycosis fungoides, the disease may progress to higher stages. The pathogenesis and risk factors of progression in mycosis fungoides and Sézary syndrome are not yet fully understood. Previous works have investigated inter- and intrapatient tumor cell heterogeneity. Here, we overview the role of the tumor microenvironment of mycosis fungoides and Sézary syndrome by describing its key components and functions. Emphasis is put on the role of the microenvironment in promoting tumor growth or antitumor immune response, as well as possible therapeutic targets. We focus on recent advances in the field and point out treatment-related alterations of the microenvironment. Deciphering the tumor microenvironment may help to develop strategies that lead to long-term disease control and cure.

SUBMITTER: Dobos G

PROVIDER: S-EPMC9913729 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Mycosis Fungoides and Sézary Syndrome: Microenvironment and Cancer Progression.

Dobos Gabor G Lazaridou Ingrid I de Masson Adèle A

Cancers 20230125 3

Mycosis fungoides and Sézary syndrome are epidermotropic cutaneous lymphomas, and both of them are rare diseases. Mycosis fungoides is the most frequent primary cutaneous lymphoma. In about 25% of patients with mycosis fungoides, the disease may progress to higher stages. The pathogenesis and risk factors of progression in mycosis fungoides and Sézary syndrome are not yet fully understood. Previous works have investigated inter- and intrapatient tumor cell heterogeneity. Here, we overview the ro ...[more]

PMID: 36765704

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Mycosis fungoides and Sezary syndrome.

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Project description:Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

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Denileukin diftitox for the treatment of CD25 low-expression mycosis fungoides and Sezary syndrome.

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PD-1 improves accurate detection of Sezary cells by flow cytometry in peripheral blood in mycosis fungoides/Sezary syndrome.

Project description:BackgroundAccurate Sezary cell detection in peripheral blood of mycosis fungoides/Sezary syndrome (MF/SS) patients by flow cytometry can be difficult due to overlapping immunophenotypes with normal T cells using standard markers. We assessed the utility of programmed death-1 (PD-1/CD279), a transmembrane protein expressed in some hematopoietic cells, for identification and quantitation of circulating Sezary cells among established markers using flow cytometry.Methods50 MF/SS and 20 control blood samples were immunophenotyped by flow cytometry. Principal component analysis (PCA) assessed contributions of antigens to separation of abnormal from normal T cell populations. PD-1 was assessed over time in blood and bone marrow of available MF/SS cases.ResultsNormal CD4+ T cells showed dim/intermediate to absent PD-1 expression. PD-1 in Sezary cells was informatively brighter (≥1/3 log) than internal normal CD4+ T cells in 39/50 (78%) cases. By PCA, PD-1 ranked 3rd behind CD7 and CD26 in population separation as a whole; it ranked in the top 3 markers in 32/50 (64%) cases and 1st in 4/50 (8%) cases when individual abnormal populations were compared to total normal CD4+ T cells. PD-1 clearly separated Sezary from normal CD4+ T cells in 15/26 (58%, 30% of total) cases with few and subtle alterations of pan-T cell antigens/CD26 and was critical in 6 (12% of total), without which identification and quantification were significantly affected or nearly impossible. PD-1 remained informative in blood/bone marrow over time in most patients.ConclusionsPD-1 significantly contributes to accurate flow cytometric Sezary cell assessment in a routine Sezary panel.

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Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sezary Syndrome: A Multicenter Phase II Study.

Project description:PurposeTo assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).Patients and methodsCITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.ResultsPatients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature.ConclusionPembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.

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