Disruption of enhancer network prevent MDSC generation and promote mature myeloid cell differentiation
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摘要Myeloid derived suppressor cell (MDSC) is a population of immature myeloid cells that undermine immune surveillance and facilitate tumor immune escape and progression. Preventing the generation of MDSC, therefore, is worthwhile to restore immune response in the immunosuppressive tumor microenvironment. Most hepatocellular carcinorma (HCC) arise in a context of chronic inflammation associated with fibrosis, with aberrant hepatic stellate cell activation (HSC). Activated HSCs was widely reported to induce MDSC generation through cell-cell contact and/or secreted soluble factors, which counteract immune system and establish favorable “soil” for liver tumor formation. Understanding the underlying mechanisms involved in HSC-induced MDSC generation is meaningful to develop efficient strategies to prevent MDSC accumulation in HCC patients. Given the crucial role of enhancer in cell lineage specification, we aim to elucidate whether enhancer network participate in HSC induced MDSC generation. Comprehensive epigenetic drugs screening and expression analysis suggested the important role of active enhancer mark, histone 3 lysine 27 acetylation (H3K27ac) in MDSC, which increased during HSC-induced MDSC generation process. Disruption of enhancer network by BET inhibitor JQ1, abrogates MDSC generation and suppressive function. Further mechanistic studies showed that, BET inhibition prevent HSC induced C/EBPβ and p-STAT3 upregulation in MDSC, which are two critical transcription factors mediating MDSC generation. Besides, IL-6, IL-Iβ, S100A8, S100A9 and S100A12 pro-inflammatory proteins, which highly expressed in HSC-induced MDSCs, also decreased upon BET inhibition. Furthermore, immune profiling analysis showed higher numbers of mature dendritic cells and macrophages were observed upon JQ1 treatment, with increased co-stimulatory molecules like CD40, CD80, CD86 expression on their surface, reflecting their increased maturation stage toward antigen-presenting cells (APCs). Above studies showed that disruption of enhancer network could not only prevent MDSC generation, but also promote MDSC to differentiate into mature myeloid cells. These results warrant the further identification of HSC-activated enhancers that orchestrate MDSC identity and functions, which may provide novel therapeutic targets to restore effective anti-tumor immune response in HCC patients.
著者Liu M, Cheng SL, Zhou J, Wu F
會議名稱The 3rd Taiwan Epigenomics Symposium and International Conference on Systems Biology

上次更新時間 2018-20-01 於 19:20