Enhancer dysregulation of myeloid-derived suppressor cells in hepatocellular carcinoma
Refereed conference paper presented and published in conference proceedings


摘要Hepatocellular carcinoma (HCC) is the most common liver cancer. The suppressive tumor microenvironment (TME) plays an instrumental role in HCC development and progression. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which are the major component of TME that undermine immune surveillance and facilitate tumor progression and immune escape. Given that enhancers can alter local chromatin state for gene transcriptional outputs play a crucial role in cell lineage specification, we aim to elucidate the enhancer regulation of MDSC identity and function in the immunosuppressive liver TME.

Using human peripheral blood mononuclear cells (PBMCs) from healthy donors, we have successfully recapitulated the immunomodulatory effect of hepatic stellate cell (HSC) on MDSC generation. Using single cell-RNA sequencing from HCC patient samples and RNA sequencing from in vitro-derived MDSCs, a panel of signature genes which have aberrant overexpression in MDSC were identified. Among which some of the signature genes are controlled by enhancers, which was predicted by FANTOM5 and verified by histone lysine 27 acetylation (H3K27ac) occupancy through chromatin immunoprecipitation (ChIP)-qPCR. Comprehensive epigenetic drug screening and expression analysis suggested that H3K27ac, an active enhancer histone mark contributes to HSC-induced MDSC generation, supporting the role of enhancers in controlling MDSC identity. We further demonstrated that bromodomain and extraterminal domain (BET) inhibitor JQ1, which disrupts bromodomain protein 4 (BRD4) association with H3K27ac-enriched active enhancers, controls MDSC signature gene expressions and abrogates MDSC generation and T cell suppressive function.
These results reveal that enhancers are crucial in MDSC identity formation and function, which may provide novel therapeutic targets to restore the anti-tumor immune response in HCC patients.
著者Wing Yan LAW, Man LIU, Ka Wing CHEUNG, Jingying ZHOU, Alfred Sze Lok CHENG
會議名稱CSH-Asia Conference: Advances in Cancer Immunology

上次更新時間 2020-18-05 於 15:49