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Genome-wide transcriptome analysis of the STAT6-regulated genes in advanced-stage cutaneous T-cell lymphoma [scRNA-seq]

ABSTRACT: The signal transducer and activator of transcription 6 (STAT-6) is a critical up-stream mediator of IL-13 and IL-4 signaling and is constitutively activated in malignant lymphocytes from Sezary syndrome (SS) and mycosis fungoides (MF), the most common subtypes of cutaneous T-cell lymphomas. By combining genome-wide expression profiling with pharmacological STAT-6 inhibition, we have identified the genes regulated by STAT-6 in MF/SS tumors. We found that STAT-6 regulates several common pathways in MF/SS malignant lymphocytes that are associated with control of cell cycle progression and genomic stability as well as production of Th2 cytokines. Using ex vivo skin explants from cutaneous MF tumors as well as Sezary cells derived from the blood of SS patients, we demonstrated that inhibition of STAT-6 activation down-regulates cytokine production and induces cell cycle arrest in MF/SS malignant lymphocytes, inhibiting their proliferation but not their survival. Furthermore, we show that STAT-6 promotes the pro-tumoral M2-like phenotype of tumor-associated macrophages in the tumor microenvironment of advanced-stage MF by up-regulating the expression of genes associated with immunosuppression, chemotaxis, and tumor matrix remodeling. Thus, we show STAT-6 to be a major factor in the pathogenesis and progression of MF/SS, promoting proliferation and invasion of the malignant lymphocytes while inducing a progressive depression of the anti-tumor immune response. Together, our results provide new insights into disease pathogenesis and offer new prospective targets for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147944 | GEO | 2020/10/22

REPOSITORIES: GEO

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Genome-wide transcriptome analysis of the STAT6-regulated genes in advanced-stage cutaneous T-cell lymphoma [Bulk-seq]

Project description:The signal transducer and activator of transcription 6 (STAT-6) is a critical up-stream mediator of IL-13 and IL-4 signaling and is constitutively activated in malignant lymphocytes from Sezary syndrome (SS) and mycosis fungoides (MF), the most common subtypes of cutaneous T-cell lymphomas. By combining genome-wide expression profiling with pharmacological STAT-6 inhibition, we have identified the genes regulated by STAT-6 in MF/SS tumors. We found that STAT-6 regulates several common pathways in MF/SS malignant lymphocytes that are associated with control of cell cycle progression and genomic stability as well as production of Th2 cytokines. Using ex vivo skin explants from cutaneous MF tumors as well as Sezary cells derived from the blood of SS patients, we demonstrated that inhibition of STAT-6 activation down-regulates cytokine production and induces cell cycle arrest in MF/SS malignant lymphocytes, inhibiting their proliferation but not their survival. Furthermore, we show that STAT-6 promotes the pro-tumoral M2-like phenotype of tumor-associated macrophages in the tumor microenvironment of advanced-stage MF by up-regulating the expression of genes associated with immunosuppression, chemotaxis, and tumor matrix remodeling. Thus, we show STAT-6 to be a major factor in the pathogenesis and progression of MF/SS, promoting proliferation and invasion of the malignant lymphocytes while inducing a progressive depression of the anti-tumor immune response. Together, our results provide new insights into disease pathogenesis and offer new prospective targets for therapeutic intervention.

2020-10-22 | GSE147911 | GEO

Deciphering Tumor Cell Evolution in Cutaneous T-Cell Lymphomas: Distinct Differentiation Trajectories in Mycosis Fungoides and Sézary Syndrome

Project description:Cutaneous T-cell lymphomas are a heterogeneous group of neoplasms originating in the skin, with mycosis fungoides (MF) and Sézary syndrome (SS) representing the most common variants. The cellular origin of cutaneous lymphomas has remained controversial due to their immense phenotypic heterogeneity that obfuscates lineage reconstruction based on classical surface biomarkers. To overcome this heterogeneity and reconstruct the differentiation trajectory of malignant cells in MF and SS, T-cell receptor sequencing was performed in parallel with targeted transcriptomics at the single-cell resolution among cutaneous samples in MF and SS. Unsupervised lineage reconstruction showed that Sézary cells exist as a population of CD4+ T cells distinct from those in patch, plaque, and tumor MF. Further investigation of malignant cell heterogeneity in SS showed that Sézary cells phenotypically comprised at least three subsets based on differential proliferation potentials and expression of exhaustion markers. A Th1 polarized cell type, intermediate cell type, and exhausted Th2 polarized cell type were identified, with Th1 and Th2 polarized cells displaying divergent proliferation potentials. Collectively, these findings provide evidence to clarify the relationship between MF and SS, and reveal cell subsets in SS that suggest a possible mechanism for therapeutic resistance.

2022-12-31 | GSE192836 | GEO

CD164 and FCRL3 are highly expressed on CD4+CD26- T cells in Sezary syndrome; inverse correlation between CD164 and CD26 expression

Project description:Sezary syndrome (SS) represents a leukemic variant of cutaneous T cell lymphoma (CTCL) with circulating malignant CD4 T cells trafficking to the skin. The cell surface molecules present on malignant cells are also expressed on normal CD4 T cells. Therefore, we attempted to find a specific marker for malignant cells that would distinguish them from normal cells. Comprehensive microarray analysis of gene expression in the malignant cells indicated significantly increased levels of mRNA for cell surface markers CD164, a sialomucin found on human CD34+ hematopoietic stem cells, as well as FCRL3, a molecule present on a subset of human natural T regulatory cells. Both markers were increased in CD4 T cells from the SS patients compared to those from Mycosis Fungoides patients and healthy volunteers. Subsequent studies utilizing QPCR and flow cytometry confirmed the increased expression of CD164 and FCRL3 mainly in CD4+CD26- T cells of SS patients. Our results suggest that CD164 can serve as a marker for diagnosis as well as disease monitoring of CTCL/SS, whereas the FCRL3 expression correlates with disease progression.

2019-11-21 | GSE39041 | GEO

Characterization of the cutaneous tumor microenvironment of advanced-stage mycosis fungoides using single-cell RNA sequencing

Project description:Malignant T lymphocyte proliferation in mycosis fungoides (MF) is largely restricted to the skin, implying that malignant cells are dependent on their specific cutaneous tumor microenvironment (TME), including interactions with non-malignant immune and stromal cells, cytokines, and other immunomodulatory factors. To explore these interactions, we performed a comprehensive transcriptome analysis of the TME in advanced-stage MF skin tumors by single-cell RNA sequencing. Our analysis identified cell-type compositions, cellular functions, and cell-cell interactions in the MF TME that were distinct from those from healthy skin and benign dermatoses. While patterns of gene expression were common amongst patient samples, high transcriptional diversity was also observed in immune and stromal cells, with dynamic interactions and crosstalk between these cells and malignant T lymphocytes. This heterogeneity mapped to processes such as cell trafficking, matrix interactions, angiogenesis, immune functions, and metabolism that affect cancer cell growth, migration and invasion, as well as anti-tumor immunity. By comprehensively characterizing the transcriptomes of immune and stromal cell within the cutaneous microenvironment of individual MF tumors, we have identified patterns of dysfunction common to all tumors that represents a resource for identifying candidates with therapeutic potential as well as patient-specific heterogeneity that has important implications for personalized disease management.

2023-11-21 | GSE206123 | GEO

Microenvironment-dependent growth of Sezary cells in humanized IL-15 mice [scRNA/TCR-seq]

Project description: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 and survival factor. Importantly, a genetically engineered immunodeficient mouse model expressing human IL-15 uniquely supported the growth of patient derived Sezary cells relative to conventional immunodeficient mouse strains. Patient derived xenograft (PDX) SS models recapacitated the 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 transcriptome analysis revealed tissue specific regulation of gene expression and distinct clonal engraftment patterns. Overall, we document an important dependence of Sezary cell survival and proliferation on IL-15 signaling and the utility of the humanized IL-15, immunodeficient mice for SS PDX model generation. Furthermore, these studies advocate for the thorough molecular understanding of the resultant PDX models to maximize their translational impact.

2023-09-29 | GSE229406 | GEO

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

2023-09-29 | GSE227326 | GEO

Single-cell RNA sequencing unveils the clonal and transcriptional landscape of cutaneous T-cell lymphomas

Project description:Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma, arising from clonal expansion of transformed skin-homing memory T cells. However, the lack of specific markers for malignant lymphocytes prevents distinguishing them from benign T cells in the tumor microenvironment (TME) of MF, thus delaying diagnosis and development of specific treatment, which results in poor clinical outcomes. Here we employed recent advances in single-cell RNA-sequencing to establish the transcriptome of expanded T-cell clones directly in advanced-stage MF skin tumors, allowing the transcriptional profiles of malignant and reactive T lymphocytes to be distinguished. Our analysis identified multiple non-overlapping expanded T-cell clonotypes within individual MF tumors, which included malignant and reactive clones. Heterogeneity among samples was observed not only in the number of expanded clonotypes but also in their TCR specificity and gene expression. While patient-specific tumorigenic pathways were up-regulated by the malignant clones, we also identified a common gene expression that included genes associated with cancer cell metabolism, de novo nucleotide biosynthesis, and invasion. Most non-malignant clones originated from CD8+ T cells and commonly presented an exhausted immune phenotype and activated Th1/Th2 pathways. While non-clonal infiltrating CD4+ and CD8+ lymphocytes from all tumors shared anti-inflammatory and immunosuppressive pathways, patient-specific mechanisms included the TNFR2 signaling cascade, ferroptosis, and cytotoxic pathways by gamma/delta T cells. Thus, scRNAseq reveals new insights in MF pathogenesis by providing an unprecedented report of the transcriptomes of malignant and reactive T cells in the TME of individual patients and offers novel prospective targets for personalized therapy.

2022-06-01 | GSE182861 | GEO

Mycosis fungoides

Project description:Mycosis fungoides (MF) is the most common and best studied of cutaneous T-cell lymphoma (CTCL). Three clinical cutaneous stages have been described (patch, plaque and tumor) as the disease progress developing also the disease lymph node, peripheral blood or systemic involvement in late stages. Clinical and pathologic diagnosis of early MF stages (patch and plaque) is difficult as its morphologic similarity to inflammatory dermatoses and low proportion of tumoral cells.

2018-06-21 | GSE109421 | GEO

Whole-genome and transcriptome sequencing of tumor-stage mycosis fungoides

Project description:Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL), a group of malignancies derived from skin-homing malignant T cells. We subjected tumor biopsies from MF patients to whole-genome sequencing and RNA-sequencing to investigate genomic alterations and deregulated gene expression in the disease.

| EGAS00001002860 | EGA

Single-cell RNA sequencing comparison of CD4+, CD8+ and T-cell receptor γδ+ cutaneous T-cell lymphomas reveals subset-specific molecular phenotypes

Project description:Background: Malignant clones of primary cutaneous T-cell lymphomas (CTCL) can show a CD4+, CD8+ or T-cell receptor γδ+ phenotype, but their individual impact on tumor biology and skin lesion formation remains ill-defined. We perform a comprehensive molecular characterization of CD4+ vs. CD8+ and TCR-γ/δ+ CTCL lesions. Methods: We performed scRNA-seq of 18 CTCL skin biopsies to compare classic CD4+ advanced-stage mycosis fungoides (MF) with TCR-γ/δ+ MF and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (Berti’s lymphoma). Results: Malignant clones of TCR-γ/δ+ MF and Berti’s lymphoma showed similar clustering patterns distinct from CD4+ MF, along with increased expression of cytotoxic markers such as NKG7, CTSW, GZMA, and GZMM. Only advanced-stage CD4+MF clones expressed central memory T-cell markers (SELL, CCR7, LEF1), alongside B1/B2 blood involvement, whereas TCR-γ/δ+ MF and Berti’s lymphoma harbored a more tissue-resident phenotype (CD69, CXCR4, NR4A1) without detectable cells in the blood. CD4+ MF and TCR-γ/δ+ MF skin lesions harbored strong type 2 immune activation across myeloid cells, while Berti’s lymphoma was more skewed towards type 1 immune responses. Both CD4+ MF and TCR-γ/δ+ MF lesions showed upregulation of keratinocyte hyperactivation markers such as S100As and KRT16 genes. This increase was entirely absent in Berti’s lymphoma, possibly reflecting an aberrant keratinocyte response to invading tumor cells, that could contribute to the formation of the typical ulcero-necrotic lesions within this entity. Conclusions: Our scRNAseq profiling study reveals specific molecular patterns associated with distinct CTCL subtypes.

2024-10-24 | GSE266862 | GEO

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