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Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma
Gut ( IF 23.0 ) Pub Date : 2019-05-10 , DOI: 10.1136/gutjnl-2018-317257
Man Liu 1, 2 , Jingying Zhou 1 , Xiaoyu Liu 1 , Yu Feng 1 , Weiqin Yang 1 , Feng Wu 3 , Otto Ka-Wing Cheung 1 , Hanyong Sun 4, 5 , Xuezhen Zeng 1 , Wenshu Tang 1 , Myth T S Mok 1 , John Wong 6 , Philip Chun Yeung 6 , Paul Bo San Lai 6 , Zhiwei Chen 7 , Hongchuan Jin 8 , Jie Chen 2 , Stephen Lam Chan 9 , Anthony W H Chan 3 , Ka Fai To 3, 10 , Joseph J Y Sung 4, 11 , Minhu Chen 2 , Alfred Sze-Lok Cheng 1, 11
Affiliation  

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.

中文翻译:

靶向单核细胞内在增强子重编程可提高肝细胞癌的免疫治疗效果

目的肝细胞癌(HCC)主要发生在纤维化/肝硬化的肝脏,对免疫检查点阻断(ICB)治疗的反应性相对较低。由于髓源性抑制细胞 (MDSC) 是免疫抑制的关键,我们研究了其在纤维化微环境中的作用和调节,目的是开发基于机制的联合免疫疗法。设计 MDSCs 的功能意义通过流式细胞术在纤维化肝脏环境中使用两种原位 HCC 模型通过四氯化碳或高脂肪高碳水化合物饮食进行评估,并通过临床标本进行验证。在人肝星状细胞 (HSC)-外周血单核细胞培养系统和纤维化-HCC 患者来源的 MDSC 中进行了机制研究。确定了使用抗程序性死亡 1-配体-1(抗 PD-L1)和临床试验的 BET 溴结构域抑制剂 i-BET762 进行单一或联合治疗的疗效。结果 纤维化肝脏中单核细胞 MDSC (M-MDSC) 而非多形核 MDSC 的积累与两种小鼠模型中肿瘤浸润淋巴细胞 (TIL) 减少和致瘤性增加显着相关。在人类 HCC 中,肿瘤周围的纤维化肝脏显着富含 M-MDSC,其替代标志物 CD33 与侵袭性肿瘤表型和低存活率显着相关。从机制上讲,活化的 HSC 诱导单核细胞内在 p38 MAPK 信号传导以触发增强子重编程,用于 M-MDSC 发育和免疫抑制。用 p38 MAPK 抑制剂治疗消除了 HSC-M-MDSC 串扰以防止 HCC 生长。伴随 i-BET762 对患者来源的 M-MDSC 的抑制,与抗 PD-L1 联合治疗协同增强 TIL,从而在纤维化 HCC 小鼠模型中根除肿瘤并延长生存期。结论我们的结果表明如何利用促纤维化微环境中的非肿瘤内在特性来恢复免疫监视,提供易于翻译的组合策略来增强 HCC 免疫治疗。
更新日期:2019-05-10
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