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Senescent Langerhans cell histiocytosis cells arise from both dendritic cell (DC) and monocyte/DC3 lineages

ABSTRACT: Langerhans cell histiocytosis (LCH) is a potentially fatal myeloid neoplasia, stemming from the mononuclear phagocyte (MNP) system. Discrimination of neoplastic cells that share features with normal MNPs is essential for mapping disease origin and pathogenesis. Here, we performed a deep profiling of LCH cells combining single cell RNA-seq and protein analysis enabling us to assess their heterogeneity and compare to their normal counterparts within the tumor microenvironment. Downstream analysis revealed LCH signatures pointing to senescence and tumor immune surveillance escape mechanisms. Developmentally, two major LCH arms, phenotypically resembling DC2 and monocyte/DC3 lineages, were identified and validated in situ across different pathological tissue sites using high-throughput microscopy. The present results support a dual origin model of LCH with an underlying neoplastic hit prior to the fate commitment to DC2 and monocyte/DC3 lineages, and provides basis for development of future targets in LCH and other histiocytic disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173923 | GEO | 2022/12/09

REPOSITORIES: GEO

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Project description:Langerhans-cell histiocytosis (LCH) is characterized by heterogeneous lesions containing CD207+ Langerhans cells (LCs) and lymphocytes. In this study, we isolated CD207+ cells and CD3+ T cells from LCH lesions to determine cell-specific gene expression. Compared to control epidermal CD207+ cells, the LCH CD207+ cells yielded 2113 differentially-expressed genes (FDR<0.01). Surprisingly, expression of many genes previously associated with LCH, including cell-cycle regulators, pro-inflammatory cytokines and chemokines were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly over-expressed in LCH CD207+ cells. Furthermore, several genes associated with immature myeloid dendritic cells were over-expressed in LCH CD207+ cells. Compared to the peripheral CD3+ cells from LCH patients, the LCH lesion CD3+ cells yielded only 162 differentially-regulated genes (FDR<0.01), and the expression profile of the LCH lesion CD3+ cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4 as well as SPP1. Based on these results, we propose a new model of LCH pathogenesis in which lesions do not arise from epidermal Langerhans cells, but from accumulation of bone-marrow derived immature myeloid dendritic cells that recruit activated lymphocytes. Cell-specific gene expression from LCH biopsy specimens was evaluated by comparing hybridization signal from amplified cDNA on Affymetrix gene chips (U133A Plus 2.0) (Table1). Three sets of comparisons were performed: 1) Thirteen LCH CD207+ samples were compared to 12 control skin LCH CD207+ samples. 2) Seven LCH lesion CD3+ samples were compared to 7 peripheral blood CD3+ samples from the same patients. 3) Twelve LCH lesion CD3+ samples were compared to 4 pooled control tonsil CD3+ samples (5 individual tonsil CD3+ samples/pool).

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Senescent Langerhans cell histiocytosis cells arise from both dendritic cell (DC) and monocyte/DC3 lineages

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