Delineating the epigenetic regulation of myeloid derived suppressor cell generation in hepatocellular carcinoma associated with cirrhosis
Refereed conference paper presented and published in conference proceedings


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AbstractHepatocellular carcinoma (HCC) is the most common liver tumor with dismal prognosis. Since most liver tumors arise in a context of chronic inflammation associated with fibrosis, tumor microenvironment plays a critical role in liver carcinogenesis. Myeloid derived suppressor cell (MDSC) is a population of immature myeloid cells that undermine immune surveillance and facilitate tumor immune escape. As a key driver of liver fibrosis, activated hepatic stellate cell (HSC) has been recently shown to induce MDSC generation through cell-cell contact and/or secreted soluble factors. Given the crucial role of epigenetics in cell lineage specification, we aim to elucidate the chromatin regulation of MDSC in the immunosuppressive liver tumor microenvironment. Using human PBMCs from healthy donors, we have successfully recapitulated the immunomodulatory effect of HSCs on monocytic MDSC generation. Comprehensive epigenetic drug screening and expression analysis indicated that accumulation of histone H3 lysine 27 acetylation (H3K27ac), an active enhancer histone mark, is involved in the process of HSC-induced MDSC generation. We further demonstrated that inhibitors of BET family, which disrupts BRD4 association with H3K27ac-enriched active enhancers, abrogates MDSC generation. These results highlight the importance of epigenetic regulation in MDSC accumulation in the fibrotic microenvironment. Ongoing work is directed towards the identification of HSC-activated enhancers that orchestrate MDSC identity and functions. As we showed high level of monocytic MDSC accumulation in patients with cirrhotic HCC, our study may provide novel therapeutic targets to restore effective anti-tumor immune response in this dreadful disease.
All Author(s) ListMan Liu, Jingying Zhou, John Wong, Anthony W.H. Chan, Zhiwei Chen, Alfred Sze Lok Cheng
Name of Conference2017 AAI conference
Start Date of Conference12/05/2017
End Date of Conference16/05/2017
Place of ConferenceWashington
Country/Region of ConferenceUnited States of America
Proceedings TitleThe Journal of Immunology
Year2017
Month5
Volume Number198
Issue NumberSuppl. 1
PublisherThe American Association of Immunologists, Inc.
Pages205.14
ISSN0022-1767
eISSN1550-6606
LanguagesEnglish-United States

Last updated on 2018-20-01 at 19:55