Fibroblasts in Nodular Sclerosing Classical Hodgkin Lymphoma Are Defined by a Specific Phenotype and Protect Tumor Cells From Brentuximab-Vedotin Induced Injury
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE153517 | GEO | 2020/06/30
REPOSITORIES: GEO
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Project description:The cellular microenvironment in classical Hodgkin lymphoma (cHL) is dominated by a mixed infiltrate of inflammatory cells with typically only about 1% Hodgkin and Reed/Sternberg (HRS) tumor cells. T cells are usually the largest population of cells in the cHL microenvironment, encompassing T helper (Th) cells, regulatory T (Treg) cells and cytotoxic T cells. Th and Treg cells presumably provide essential survival signals for HRS cells. Treg cells are also involved in rescuing HRS cells from anti-tumor immune responses. An understanding of the immune evasion strategies of HRS cells is not only highly relevant for a characterization of the pathophysiology of cHL, but also clinically, given the current treatment approaches targeting checkpoint inhibitors. Here, we characterized the cHL-specific CD4+ T cell infiltrate regarding its role in immune evasion. Global gene expression analysis of CD4+ Th and Treg cells isolated from cHL lymph nodes and reactive tonsils revealed that Treg cell signatures were enriched in CD4+ Th cells of cHL. Hence, HRS cells may induce a Treg differentiation in Th cells, which was supported by in vitro studies with Th cells and cHL cell lines. Furthermore, we found indication for immune-suppressive purinergic signaling and a role of the inhibitory receptor-ligand pairs BTLA-HVEM and CD200R-CD200 in promoting immune evasion. Taken together, this study reveals that the immune evasion strategies in cHL are even more complex and multifaceted than previously recognized.
2017-10-09 | GSE102693 | GEO
Project description:The pathogenesis of classical Hodgkin lymphoma (cHL), the most common lymphoma in the young, is still enigmatic, largely because its Hodgkin and Reed-Sternberg (HRS) tumor cells are rare in the involved lymph node and therefore difficult to analyze. Here, by overcoming this technical challenge and performing for the first time a genome-wide transcriptional analysis of microdissected HRS cells in comparison to other B-cell lymphomas, cHL lines and normal B-cell subsets, we show that they differ extensively from the usually studied cHL cell lines, that the lost B-cell identity of cHLs is not linked to the acquisition of a plasma cell-like gene expression program, and that Epstein-Barr virus infection of HRS cells has a minor transcriptional influence on the established cHL clone. Moreover, although cHL appears a distinct lymphoma entity overall, HRS cells of its histological subtypes diverged in their similarity to other related lymphomas. Unexpectedly, we identified two molecular subgroups of cHL associated to differential strengths of the transcription factor activity of the NOTCH1, MYC and IRF4 proto-oncogenes. Finally, HRS cells display deregulated expression of several genes potentially highly relevant to lymphoma pathogenesis, including silencing of the apoptosis-inducer BIK and of INPP5D, an inhibitor of the PI3K-driven oncogenic pathway.
2012-09-17 | GSE40160 | GEO
Project description:The pathogenesis of classical Hodgkin lymphoma (cHL), the most common lymphoma in the young, is still enigmatic, largely because its Hodgkin and Reed-Sternberg (HRS) tumor cells are rare in the involved lymph node and therefore difficult to analyze. Here, by overcoming this technical challenge and performing for the first time a genome-wide transcriptional analysis of microdissected HRS cells in comparison to other B-cell lymphomas, cHL lines and normal B-cell subsets, we show that they differ extensively from the usually studied cHL cell lines, that the lost B-cell identity of cHLs is not linked to the acquisition of a plasma cell-like gene expression program, and that Epstein-Barr virus infection of HRS cells has a minor transcriptional influence on the established cHL clone. Moreover, although cHL appears a distinct lymphoma entity overall, HRS cells of its histological subtypes diverged in their similarity to other related lymphomas. Unexpectedly, we identified two molecular subgroups of cHL associated to differential strengths of the transcription factor activity of the NOTCH1, MYC and IRF4 proto-oncogenes. Finally, HRS cells display deregulated expression of several genes potentially highly relevant to lymphoma pathogenesis, including silencing of the apoptosis-inducer BIK and of INPP5D, an inhibitor of the PI3K-driven oncogenic pathway. The present study complements the GSE12453 and GSE14879 records by adding the following 10 samples: 5 primary tumor samples and 5 cell line samples. The 5 primary tumor samples represent 1000-2000 neoplastic cells microdissected from frozen biopsies of 5 cases of primary mediastinal B-cell lymphoma (PMBL). The 5 cell line samples represent 500-1000 living neoplastic cells isolated by fluorescence-activated cell sorting from growing cultures of the classical Hodgkin lymphoma (cHL) cell lines L1236, L428, KMH2 and HDLM2 and the lymphocyte-predominant Hodgkin lymphoma (lpHL) cell line DEV.
2012-09-17 | E-GEOD-40160 | biostudies-arrayexpress
Project description:A unique feature of the tumour cells (Hodgkin/Reed-Sternberg (HRS)) of classical Hodgkin lymphoma (cHL) is the loss of their B-cell phenotype despite their B-cell origin. Several lines of evidence suggest that epigenomic events, especially promoter DNA-methylation, are involved in this silencing of many B-cell associated genes. Here we show that DNA-demethylation alone or in conjunction with histone-acetylation is not able to reconstitute the B-cell gene expression program in cultured HRS cells. Instead, combined DNA-demethylation and histone-acetylation of B cells induce a nearly complete extinction of their B-cell expression program and a tremendous up-regulation of numerous cHL characteristic genes including key players such as Id2 known to be involved in the suppression of the B-cell phenotype. Since the up-regulation of cHL characteristic genes and the extinction of the B-cell expression program occurred simultaneously, epigenetic changes may also be responsible for the malignant transformation of cHL. The epigenetic up-regulation of cHL characteristic genes thus play - in addition to promoter DNA-hypermethylation of B-cell associated genes – a pivotal role for the reprogramming of HRS cells and explain why DNA-demethylation alone is unable to reconstitute the B-cell expression program in HRS cells. Keywords: Epigenetic modification
2007-11-01 | GSE8388 | GEO
Project description:The classical Hodgkin lymphoma (cHL) environment is comprised of a rich and varied immune cell infiltrate that is co-opted to support the survival and growth of malignant Hodgkin-Reed-Sternberg (HRS) cells. Several lines of evidence support the notion that, despite the immune suppressive environment that characterizes this disease, HRS cells are actively surveilled by endogenous T cells. For instance, HRS cells recurrently acquire genetic lesions associated with impaired antigen presentation and PD-L1 upregulation. Moreoever, cHL is particularly vulnerable to anti-PD-1/PD-L1 immunotherapy, which indicates that T cells can recognize and eliminate HRS cells when dominant immune checkpoints are disabled. However, the T cells that drive responses to anti-PD-1 therapy in cHL have not been defined. Furthermore, there is a paucity of data linking phenotypic and functional T cell states with clonality at the single cell level in cHL. To address this knowledge gap, we performed paired single cell RNA and T cell receptor sequencing (scRNA/TCR-seq) on 14 cHL and 5 reactive lymphoid tissue (RLT) specimens. Recurrent and significant clonal expansion within effector and exhausted CD8+ T cell and regulatory T (TREG) cell clusters was uniquely observed in most cHL specimens. Surprisingly, CD8+ T cells exhibiting transcriptional features of exhaustion were relatively uncommon in cHL specimens. Multi-plex flow cytometric analysis revealed maintained effector cytokine secretion by most conventional lymphoma-infiltrating T cells upon ex vivo restimulation, which argued against a profound T cell dysfunctional state in cHL, and suggested that lymphoma-iniltrating T cells, when removed from the immune suppressive cHL environment, are capable of exerting effector functions. Finally, these results raise new questions about the nature of the T cells that mediate response to PD-1 blockade therapy in patients with cHL.
2024-01-22 | GSE245920 | GEO
Project description:Apart from its unique histopathological appearance with rare tumor cells embedded in an inflammatory background of bystander cells, classical Hodgkin lymphoma (cHL) is characterized by an unusual activation of a broad range of signaling pathways involved in cellular activation. This includes constitutive high-level activity of nuclear factor-κB (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), activator protein-1 (AP-1) and interferon regulatory factor (IRF) transcription factors (TFs) that are physiologically only transiently activated. Here, we demonstrate that inactivation of the putative ubiquitin E3-ligase PDLIM2 contributes to this TF activation. PDLIM2 expression is lost at the mRNA and protein levels in the majority of cHL cell lines and Hodgkin and Reed–Sternberg (HRS) cells of nearly all cHL primary samples. This loss is associated with PDLIM2 genomic alterations, promoter methylation and altered splicing. Reconstitution of PDLIM2 in HRS cell lines inhibits proliferation, blocks NF-κB transcriptional activity and contributes to cHL-specific gene expression. In non-Hodgkin B-cell lines, small interfering RNA-mediated PDLIM2 knockdown results in superactivation of TFs NF-κB and AP-1 following phorbyl myristate acetate stimulation. Furthermore, expression of PDLIM2 is lost in anaplastic large cell lymphoma (ALCL) that shares key biological aspects with cHL. We conclude that inactivation of PDLIM2 is a recurrent finding in cHL and ALCL, promotes activation of inflammatory signaling pathways and thereby contributes to their pathogenesis
2016-09-13 | GSE86845 | GEO
Project description:Hodgkin lymphoma is derived from germinal center / post-germinal center B cells. To determine differentially expressed genes between Hodgkin Reed Sternberg cells and their presumed cell of origin we investigated the expression profiles of 5 commonly used Hodgkin lymphoma cell lines as compared to reactive germinal centers.
2010-12-11 | E-GEOD-25986 | biostudies-arrayexpress
Project description:Classic Hodgkin lymphoma (CHL) harbors a small number of Hodgkin-Reed-Sternberg (HRS) cells scattering among numerous lymphocytes. HRS cells are surrounded by distinct CD4+ T cells in a rosette-like manner. These CD4+ T cell rosettes play an important role in tumor microenvironment (TME) of CHL. To elucidate the interaction between HRS cells and CD4+ T cell rosettes, we performed digital spatial profiling (DSP) and compared gene expression profile between CD4+ T cell rosettes and other CD4+ cells separated from HRS cells. programed cell death-1 (PD-1) and tumor necrosis factor receptor superfamily member (TNFRSF) 4 were significantly highly expressed in CD4+ T cell rosettes than others. Immunohistochemistry confirmed PD-1 and TNFRSF4-expressing CD4+ T cell rosettes. This study introduced the new pathological approach to TME and provided deeper insight to CD4+ T cells in CHL.
2023-07-03 | GSE218703 | GEO
Project description:Classic Hodgkin lymphoma (CHL) harbors a small number of Hodgkin-Reed-Sternberg (HRS) cells scattered among numerous lymphocytes. HRS cells are surrounded by distinct CD4+ T cells in a rosette-like manner. These CD4+ T cell rosettes play an important role in the tumor microenvironment (TME) of CHL. To elucidate the interaction between HRS cells and CD4+ T cell rosettes, we completed digital spatial profiling to compare the gene expression profiles of CD4+ T cell rosettes and other CD4+ T cells separated from the HRS cells. Tumor necrosis factor receptor superfamily member (TNFRSF) 4 or OX40 showed significantly higher expression in CD4+ T cell rosettes when compared with other CD4+ T cells. Programed cell death-1 (PD-1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) tended to be highly expressed in CD4+ T cell rosettes compared to other CD4+ T cells. Immunohistochemistry revealed variable expression of these immune checkpoint molecules in the CD4+ T cell rosettes. This study introduced a new pathological approach to the TME and provided deeper insight into CD4+ T cells in CHL.
2023-07-03 | GSE227013 | GEO
Project description:Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific crosstalk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single cell resolution. Here, using single cell RNA sequencing, we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (9 cases) and nodular sclerosis (11 cases) subtypes of CHL, as well as 5 reactive lymph node controls.
| EGAS00001005541 | EGA