Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma. Issue 2 (10th May 2019)

• Record Type: Journal Article
• Authors: Liu, Man; Zhou, Jingying; Liu, Xiaoyu; Feng, Yu; Yang, Weiqin; Wu, Feng; Cheung, Otto Ka-Wing; Sun, Hanyong; Zeng, Xuezhen; Tang, Wenshu; Mok, Myth T S; Wong, John; Yeung, Philip Chun; Lai, Paul Bo San; Chen, Zhiwei; Jin, Hongchuan; Chen, Jie; Chan, Stephen Lam; Chan, Anthony W H; To, Ka Fai; Sung, Joseph J Y; Chen, Minhu; Cheng, Alfred Sze-Lok
• Is Part Of: Gut. Volume 69:Issue 2(2020)
• Page Start: 365
• Page End: 379
• Publication Date: 2019-05-10
• Subjects: cancer immunobiology -- fibrosis -- hepatocellular carcinoma -- immunotherapy -- liver immunology; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-317257
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.