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Single-cell RNAseq profiling in a patient with discordant primary cutaneous B and T cell lymphoma reveals micromilieu-driven immune skewing

ABSTRACT: Background: Primary cutaneous lymphomas comprise a heterogeneous group of B and T cell malignancies which often show an indolent course, but can progress to aggressive disease in a subset of patients. Diagnosis is often delayed due to clinical and histopathological similarities with benign inflammatory conditions. Especially during early disease, cancer cells are present at relatively low percentages in comparison to the inflammatory infiltrate, an interplay that is currently only insufficiently understood. Objectives: To improve diagnostics and perform molecular characterization of a complex type of primary cutaneous lymphoma. Methods: Single-cell RNA sequencing (scRNA-seq) combined with T and B cell receptor sequencing. Results: We were able to diagnose a patient with concurrent mycosis fungoides (MF) and primary cutaneous follicle center lymphoma (PCFCL), appearing in mutually exclusive skin lesions. Profiling of tumor cells and the tissue microenvironment revealed a type-2 immune skewing in MF, most likely guided by the expanded clone that also harbored upregulation of numerous pro-oncogenic genes. By contrast, PCFCL lesions exhibited a more type-1 immune phenotype, consistent with its indolent behavior. Conclusions: These data not only illustrate the diagnostic potential of scRNA-seq, but also allow the characterization of specific clonal populations shaping the unique tissue microenvironment in clinically distinct types of lymphoma skin lesions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173820 | GEO | 2021/05/25

REPOSITORIES: GEO

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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

Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma

Project description:Background: In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20-30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood. Methods: In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, and compared results with early-stage MF as well as nonlesional MF and healthy control skin. Results: Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of the tissue residency markers CXCR4 and CD69, the heat shock protein HSPA1A, the tumor suppressors and immunoregulatory mediators ZFP36 and TXNIP, and the interleukin 7 receptor (IL7R) within the malignant clone, but not in benign T cells. This phenomenon was not only found in conventional TCR-αβ MF, but also in a case of TCR-γδ MF, suggesting a common mechanism across MF subtypes. Conversely, malignant cells in clinically unaffected skin from MF patients showed upregulation of these markers. Conclusions: Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.

2021-09-13 | GSE173205 | GEO

Transcription profiling of human cutaneous B-cell lymphoma skin punch biopsies, mycosis fungoides (MF) and 3 normal skin biopsies

Project description:We studied gene expression profiles of 17 cutaneous B-cell lymphomas that were collected with 4-6 millimeter skin punch biopsies. We also included tissue from 2 cases of mycosis fungoides (MF), 3 normal skin biopsies and 3 tonsils to create a framework for further interpretation. A hierarchical cluster algorithm was applied for data analysis. Our results indicate that small amounts of skin tissue can be used successfully to perform microarray analysis and result in distinct gene expression patterns. Duplicate specimens clustered together demonstrating a reproducible technique. Within the cutaneous B-cell lymphoma specimens two specific B-cell differentiation stage signatures of germinal center B-cells and plasma cells could be identified. Primary cutaneous follicular and primary cutaneous diffuse large B-cell lymphomas had a germinal center B-cell signature while a subset of marginal zone lymphomas demonstrated a plasma cell signature. Primary and secondary follicular B-cell lymphoma of the skin were closely related, despite previously reported genetic and phenotypic differences. In contrast primary and secondary cutaneous diffuse large B-cell lymphoma were less related to each other. This pilot study allows a first glance into the complex and unique microenvironment of B-cell lymphomas of the skin and provides a basis for future studies, that may lead to the identification of potential histologic and prognostic markers as well as therapeutic targets.

2005-10-07 | E-SMDB-1798 | biostudies-arrayexpress

Gene Expression Profiles of cutaneous B-cell lymphoma

2005-12-16 | E-GEOD-3827 | biostudies-arrayexpress

Tumor RNA sequencing identifies a group of Mycosis Fungoides patients with failure of skin-directed therapies

Project description:Mycosis fungoides (MF), the most common type of primary cutaneous T-cell lymphoma, has a heterogeneous clinical course, and the factors determining disease progression from the indolent to the aggressive disease stages are not well known. Our previous study described prognostic groups of MF cases according to the transcription factors Twist and Zeb1. Using Twist expression, we differentiated distinct groups based on their global RNA expression. Using the same dataset with 40 formalin-fixed paraffin-embedded MF samples, we performed RNA sequencing using bioinformatics tools. Based on the consensus clustering, we defined four clusters with different disease pathologies and prognostic groups. Cluster 3 showed the shortest time to skin-directed therapy failure (p=0.031), and with Cluster 1 they included all the MF-related deaths (2/40). Cluster 3 presented a higher proportion of lymphocytic infiltrates per sample (p<0.001), with the highest percentages (>60 %) and a higher rate of CD30+ tumor cells (over 10 %, p=0.048). Cluster 3 samples also showed upregulated genes related to keratinocyte, basal cell, and melanocyte activities. This is the first study to describe the association between gene expression, tumor cell density, reactive cell infiltration, and failure of skin-directed therapies

2024-07-18 | GSE272226 | GEO

Gene Expression Profiles of cutaneous B-cell lymphoma

2005-12-17 | GSE3827 | GEO

Single cell sequencing delineates T-cell clonality and pathogenesis of the parapsoriasis disease group

Project description:Background: Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is often underdiagnosed in early stages due to similarities with benign dermatoses such as atopic dermatitis (AD). Furthermore, the delineation from so-called “parapsoriasis en plaque,” a disease that can appear either in a small- or large-plaque form, is still controversial. Here, we characterize the parapsoriasis disease spectrum. Methods: We performed single-cell RNA sequencing of skin biopsies from patients within the parapsoriasis-to-early-stage MF spectrum, stratified for small and large plaques, and compared them to AD, psoriasis and healthy control skin. Results: 6 out of 8 large-plaque lesions harbored either an expanded alpha/beta or gamma/delta T-cell clone with downregulation of CD7 expression, consistent with a diagnosis of early-stage MF. By contrast, 6 out of 7 small-plaque lesions were polyclonal in nature thereby lacking a lymphomatous phenotype, and also revealed a less inflammatory microenvironment than early-stage MF or AD. Of note, polyclonal small- and large-plaque lesions characteristically harbored a population of NPY+ innate lymphoid cells and displayed a stromal signature of complement upregulation and antimicrobial hyperresponsiveness in fibroblasts and sweat gland cells, respectively. These conditions were clearly distinct from AD or psoriasis, which uniquely harbored CD3+CRTH2+ IL13-expressing “Th2A” cells or strong type 17 inflammation, respectively. Conclusion: These data position polyclonal small- and large-plaque dermatitis lesions as a separate disease entity, that characteristically harbors a so far undescribed ILC population. We thus propose the new term “polyclonal parapsoriasis en plaque” to this kind of lesions, as they can be clearly differentiated from early and advanced-stage MF, psoriasis and AD on several cellular and molecular levels.

2024-10-24 | GSE247047 | GEO

Genetics of Cutaneous T-Cell Lymphoma

Project description:<p>Mycosis fungoides (MF) is a common extranodal T-cell lymphoma primarily arising in the skin. In early disease stages, MF presents as skin patches and plaques that in some cases may progress to tumor and disperse to lymph nodes and other internal organs. The 10-year overall survival is 50% in advanced stages. Early diagnosis is difficult as the histology overlaps with features of inflammatory skin diseases. Even when the diagnosis is established, there are no prognostic markers that predict whether the disease will be aggressive or indolent. Lastly, there are no curative treatments and MF will invariably relapse, even after aggressive chemotherapy. The disease is a diagnostic, prognostic and therapeutic challenge. The main objective of this study is to address the question of tumor heterogeneity in MF. To date, MF is considered to be monoclonal, derived from a transformed, mature memory T-cell. However, clinical observations and preliminary data suggest that MF comprises multiple subclones, which may be of importance for understanding disease evolution and resistance to therapy. We plan to address this objective using Whole Exome Sequencing (WES) of MF tissue prepared by laser microdissection (LMD).</p>

| phs001877 | dbGaP

Aurora kinase A is upregulated in cutaneous T-cell lymphoma and represents a potential therapeutic target

Project description:Cutaneous T-cell lymphomas form a heterogeneous group of non-Hodgkin lymphomas characterized by only poor prognosis in advanced stage. Despite significant progress made in the identification of novel genes and pathways involved in the pathogenesis of cutaneous lymphoma, the therapeutic value of these findings has still to be proven. Here, we demonstrate by gene expression arrays that aurora kinase A is one of highly overexpressed genes of the serine/threonine kinase in CTCL. The finding was confirmed by qualitative RT-PCR, Western blotting and immunohistochemistry in CTCL cell lines and primary patient samples. Moreover, treatment with a specific aurora kinase A inhibitor blocks cell proliferation by inducing cell cycle arrest in G2 phase as well as apoptosis in CTCL cell lines. These new data provide a promising rationale for using aurora kinase A inhibition as a therapeutic modality of CTCL. 14 lesional skin biopsies of different MF patients (patch=3, plaque=6, tumor=4) and 9 healthy controls. Comparison between Cutaneus Tcell Lymphoma Samples and Healthy Control Tissue

2015-03-31 | E-GEOD-59307 | biostudies-arrayexpress

Single-cell RNA sequencing reveals tissue compartment-specific plasticity of mycosis fungoides tumor cells

Project description:Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. While initially restricted to the skin, malignant cells can appear in blood, bone marrow and secondary lymphoid organs in later disease stages. However, only little is known about phenotypic and functional properties of malignant T cells in relationship to tissue environments over the course of disease progression. We thus profiled the tumor micromilieu in skin, blood and lymph node in a patient with advanced MF using single-cell RNA sequencing combined with V-D-J T-cell receptor sequencing. In skin, we identified clonally expanded T-cells with characteristic features of tissue-resident memory T-cells (TRM, CD69+CD27-NR4A1+RGS1+AHR+). In blood and lymph node, the malignant clones displayed a transcriptional program reminiscent of a more central memory-like phenotype (KLF2+TCF7+S1PR1+SELL+CCR7+), while retaining tissuehoming receptors (CLA, CCR10). The skin tumor microenvironment contained potentially tumor-permissive myeloid cells producing regulatory (IDO1) and Th2-associated mediators (CCL13, CCL17, CCL22). Given their expression of PVR, TNFRSF14 and CD80/CD86, they might be under direct control by TIGIT+CTLA4+CSF2+TNFSF14+ tumor cells. In sum, this study highlights the adaptive phenotypic and functional plasticity of MF tumor cell clones. Thus, the TRM-like phenotype enables long-term skin residence of MF cells. Their switch to a TCM-like phenotype with persistent skin homing molecule expression in the circulation might explain the multi-focal nature of MF.

2021-04-13 | GSE165623 | GEO

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