Gene Expression Comparison between Sézary Syndrome and Lymphocytic-Variant Hypereosinophilic Syndrome Refines Biomarkers for Sézary Syndrome

Moerman-Herzog, Andrea; Mehdi, Syed Jafar; Wong, Henry K.

doi:10.3390/cells9091992

Cited by 10 publications

(6 citation statements)

References 143 publications

(260 reference statements)

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“…Sézary cell markers were consistent with previous studies (Fig. 2a) 27–29 . We next analyzed pretreatment samples to identify the genes differentially expressed within Sézary cells between responding and non-responding patients (Fig.…”

Section: Resultssupporting

confidence: 92%

Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome

Ramchurren

Fling

et al. 2022

Preprint

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The PD-1 inhibitor pembrolizumab is effective in treating Sézary syndrome, a leukemic variant of cutaneous T-cell lymphoma. Our purpose was to investigate the effects of pembrolizumab on healthy and malignant T cells in Sézary syndrome and to discover characteristics that predict pembrolizumab response. Samples were analyzed before and after 3 weeks of pembrolizumab treatment by single-cell RNA-sequencing of 118,961 peripheral blood T cells isolated from six Sézary syndrome patients. T-cell receptor clonotyping, bulk RNA-seq signatures, and whole exome data were integrated to classify malignant T-cells and their underlying subclonal heterogeneity. We found that responses to pembrolizumab were associated with lower KIR3DL2 expression within Sézary T cells. Pembrolizumab modulated Sézary cell gene expression of T-cell activation associated genes. The CD8 effector populations included clonally expanded populations with a strong cytotoxic profile. Expansions of CD8 terminal effector and CD8 effector memory T-cell populations were observed in responding patients after treatment. We observed intrapatient Sézary cell heterogeneity including subclonal segregation of a coding mutation and copy number variation. Our study reveals differential effects of pembrolizumab in both malignant and healthy T cells. These data support further study of KIR3DL2 expression and CD8 immune populations as predictive biomarkers of pembrolizumab response in Sézary syndrome.

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Section: Resultssupporting

confidence: 92%

Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome

Ramchurren

Fling

et al. 2022

Preprint

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“…Immune analysis of the skin in SS shows a Th2 cytokine profile [10] and the malignant T cells exhibit a Th2 cytokine pattern with increased IL-4 [11]. From gene profiling studies, a unique gene expression phenotype of SS has been uncovered [12]. Gene expression changes in SS, such as decreased expression of IFN-γ, and increased expression of unique biomarker genes identified in SS such as TWIST1, and TOX are frequent and represent important features of CTCL [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma

2021

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Background Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin. The role of the skin microenvironment in MF development is unclear, but recent findings in a variety of cancers have highlighted the role of stromal fibroblasts in promoting or inhibiting tumorigenesis. Stromal fibroblasts are an important part of the cutaneous tumor microenvironment (TME) in MF. Here we describe studies into the interaction of TME-fibroblasts and malignant T cells to gain insight into their role in CTCL. Methods Skin from normal (n = 3) and MF patients (n = 3) were analyzed for FAPα by immunohistochemistry. MyLa is a CTCL cell line that retains expression of biomarkers TWIST1 and TOX that are frequently detected in CTCL patients. MyLa cells were cultured in the presence or absence of normal or MF skin derived fibroblasts for 5 days, trypsinized to detached MyL a cells, and gene expression analyzed by RT-PCR for MF biomarkers (TWIST1 and TOX), Th1 markers (IFNG, TBX21), Th2 markers (GATA3, IL16), and proliferation marker (MKI67). Purified fibroblasts were assayed for VIM and ACTA2 gene expression. Cellular senescence assay was performed to assess senescence. Results MF skin fibroblast showed increased expression of FAP-α with increasing stage compared to normal. Normal fibroblasts co-cultured with MyLa cells suppressed expression of TWIST1 (p < 0.0006), and TOX (p < 0.03), GATA3 (p < 0.02) and IL16 (p < 0.03), and increased expression of IFNG (p < 0.03) and TBX21 (p < 0.03) in MyLa cells. In contrast, MyLa cells cultured with MF fibroblasts retained high expression of TWIST1, TOX and GATA3. MF fibroblasts co-culture with MyLa cells increased expression of IL16 (p < 0.01) and IL4 (p < 0.02), and suppressed IFNG and TBX21 in MyLa cells. Furthermore, expression of MKI67 in MyLa cells was suppressed by normal fibroblasts compared to MF fibroblasts. Conclusion Skin fibroblasts represent important components of the TME in MF. In co-culture model, normal and MF fibroblasts have differential influence on T-cell phenotype in modulating expression of Th1 cytokine and CTCL biomarker genes to reveal distinct roles with implications in MF progression.

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“…Analysis of engrafted Sezary cells demonstrated that skin-resident CD4 + cells (clusters 2 and 5) clustered separately from the main spleen-resident CD4 + cell populations (clusters 0 and 1), suggesting tissue-specific regulation of gene expression programs. Genes highly expressed in clusters 2 and 4, including DUSP2 , NR4A2 , LMNA , FOS , SLC2A3 , and DUSP4 , were previously reported to be associated with Sezary leukemic cells ( Borcherding et al, 2019 ; Moerman-Herzog et al, 2020 ). Genes highly expressed in cluster 5 ( STMN1 , MKI67 ) are associated with cell proliferation.…”

Section: Resultsmentioning

confidence: 98%

Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice

Gao,

Ren,

Choonoo

et al. 2023

Disease Models &Amp; Mechanisms

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Sezary syndrome (SS) is a rare, aggressive leukemic variant of cutaneous T cell lymphoma (CTCL) that lacks adequate therapeutic options and representative small animal models. Here we demonstrate that IL-15 is a critical CTCL growth factor. Importantly, an immuno-deficient knock-in mouse model genetically engineered to express human IL-15 uniquely supported the growth of SS patient samples relative to conventional immunodeficient mouse strains. SS patient-derived xenograft (PDX) models recapacitated key pathologic features of the human disease, including skin infiltration and spread of leukemic cells to the periphery, and maintained the dependence on human IL-15 upon serial in vivo passaging. Detailed molecular characterization of the engrafted cells by single cell transcriptomic analysis revealed congruent neoplastic gene expression signatures but distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of immunodeficient humanized IL-15 mice as hosts for SS, and potentially other T and NK cell derived hematologic malignancies, PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.

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Gene Expression Comparison between Sézary Syndrome and Lymphocytic-Variant Hypereosinophilic Syndrome Refines Biomarkers for Sézary Syndrome

Cited by 10 publications

References 143 publications

Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome

Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome

Normal and cancer fibroblasts differentially regulate TWIST1, TOX and cytokine gene expression in cutaneous T-cell lymphoma

Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice

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