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

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. Deep profiling of LCH cells combining single cell RNA-seq and protein analysis to assess their heterogeneity and compare to their normal counterparts within the tumor microenvironment. >>>Submitter states that raw data will be submitted to EGA due to patient privacy concerns<<<