Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma
Publication in refereed journal

替代計量分析
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其它資訊
摘要Objective
Hepatocellular carcinoma (HCC), mostly developed in fibrotic/cirrhotic liver, exhibits relatively low responsiveness to immune checkpoint blockade (ICB) therapy. As myeloid-derived suppressor cell (MDSC) is pivotal for immunosuppression, we investigated its role and regulation in the fibrotic microenvironment with an aim of developing mechanism-based combination immunotherapy.

Design
Functional significance of MDSCs was evaluated by flow cytometry using two orthotopic HCC models in fibrotic liver setting via carbon tetrachloride or high-fat high-carbohydrate diet and verified by clinical specimens. Mechanistic studies were conducted in human hepatic stellate cell (HSC)-peripheral blood mononuclear cell culture systems and fibrotic-HCC patient-derived MDSCs. The efficacy of single or combined therapy with anti-programmed death-1-ligand-1 (anti-PD-L1) and a clinically trialled BET bromodomain inhibitor i-BET762 was determined.

Results
Accumulation of monocytic MDSCs (M-MDSCs), but not polymorphonuclear MDSCs, in fibrotic livers significantly correlated with reduced tumour-infiltrating lymphocytes (TILs) and increased tumorigenicity in both mouse models. In human HCCs, the tumour-surrounding fibrotic livers were markedly enriched with M-MDSC, with its surrogate marker CD33 significantly associated with aggressive tumour phenotypes and poor survival rates. Mechanistically, activated HSCs induced monocyte-intrinsic p38 MAPK signalling to trigger enhancer reprogramming for M-MDSC development and immunosuppression. Treatment with p38 MAPK inhibitor abrogated HSC-M-MDSC crosstalk to prevent HCC growth. Concomitant with patient-derived M-MDSC suppression by i-BET762, combined treatment with anti-PD-L1 synergistically enhanced TILs, resulting in tumour eradication and prolonged survival in the fibrotic-HCC mouse model.

Conclusion
Our results signify how non-tumour-intrinsic properties in the desmoplastic microenvironment can be exploited to reinstate immunosurveillance, providing readily translatable combination strategies to empower HCC immunotherapy.
出版社接受日期15.04.2019
著者Man LIU, Jingying ZHOU, Xiaoyu LIU, Yu FENG, Weiqin YANG, Feng WU, Otto Ka-Wing CHEUNG, Hanyong SUN, Xuezhen ZENG, Wenshu TANG, Myth T S MOK, John WONG, Philip Chun YEUNG, Paul Bo San LAI, Zhiwei CHEN, Hongchuan JIN, Jie CHEN, Stephen Lam CHAN, Anthony W H CHAN, Ka Fai TO, Joseph J Y SUNG, Minhu CHEN, Alfred Sze-Lok CHENG
期刊名稱Gut
出版年份2020
月份2
卷號69
期次2
頁次365 - 379
國際標準期刊號0017-5749
電子國際標準期刊號1468-3288
語言英式英語

上次更新時間 2020-10-08 於 03:10