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Digital Spatial Profiling of CD4+ cells in classic Hodgkin lymphoma.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227013 | GEO | 2023/07/03

REPOSITORIES: GEO

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Digital Spatial Profiling of tumor microenvironment of classic Hodgkin lymphoma.

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.

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Digital Spatial Profiling reveals tumor microenvironment of Hodgkin-like adult T-cell leukemia/lymphoma.

Project description:Hodgkin-like adult T-cell leukemia/lymphoma (ATLL) is a rare subtype of ATLL harboring human T cell lymphotropic virus type-1-infected Hodgkin-Reed-Sternberg (HRS)-like cells and small to medium CD4+ T cells, which histologically mimics classic Hodgkin lymphoma (CHL). CD30+ tumor cells or HRS cells are surrounded by CD4+ non-neoplastic T cells in a rosette-like manner in CHL. Interaction between HRS cells and surrounding CD4+ T cells is important for tumor microenvironment (TME) in CHL. Tumor microenvironment of Hodgkin-like ATLL remains unclear. Here, Digital Spatial Profiling was performed on Hodgkin-like ATLL to elucidate the interaction between HRS-like cells and CD4+ T cells in Hodgkin-like ATLL. We identified CD4+ T cells expressing co-stimulatory molecules, CD28 and inducible T cell co-stimulator (ICOS), in CD4+ T cells surrounding the HRS-like cells than in those apart from HRS-like cells. Immunohistochemistry was performed in 11 cases of Hodgkin-like ATLL, which detected distinct CD4+ T cells expressing CD28 in a rosette-like manner around HRS-like cells. HRS-like cells widely expressed CD80 and CD86, which suggested CD28-CD80/CD86 interaction was important in pathogenesis of Hodgkin-like ATLL. ICOS and immune checkpoint molecules, including T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and programmed death-1 (PD-1) were also variably expressed in CD4+ T cells surrounding HRS-like cells. Our findings provide new insights into the tumor microenvironment of Hodgkin-like ATLL and implicate a new therapeutic strategy targeting these molecules.

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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.

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Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma

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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

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