School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Gut. 2020 Feb;69(2):365-379. doi: 10.1136/gutjnl-2018-317257. Epub 2019 May 10.
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.
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.
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.
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.
肝细胞癌（HCC）主要发生在纤维化/肝硬化的肝脏中，对免疫检查点阻断（ICB）治疗的反应相对较低。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，旨在开发基于机制的联合免疫治疗。
通过使用两种在纤维化肝脏环境中的原位 HCC 模型（通过四氯化碳或高脂肪高碳水化合物饮食），通过流式细胞术评估 MDSC 的功能意义，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 中进行机制研究。测定了单用或联合使用抗程序性死亡-1 配体-1（抗 PD-L1）和一种临床试用的 BET 溴结构域抑制剂 i-BET762 的疗效。
在纤维化肝脏中，单核细胞来源的 MDSC（M-MDSC）的积累，而不是多形核 MDSC，与肿瘤浸润淋巴细胞（TILs）减少和两种小鼠模型中的肿瘤发生增加显著相关。在人类 HCC 中，肿瘤周围的纤维化肝脏明显富含 M-MDSC，其替代标志物 CD33 与侵袭性肿瘤表型和较差的生存率显著相关。从机制上讲，激活的 HSCs 诱导单核细胞内在的 p38 MAPK 信号转导，引发增强子重编程以促进 M-MDSC 的发育和免疫抑制。p38 MAPK 抑制剂的治疗消除了 HSC-M-MDSC 串扰，从而阻止了 HCC 的生长。与患者来源的 M-MDSC 抑制相结合，i-BET762 联合抗 PD-L1 治疗协同增强了 TILs，导致纤维化-HCC 小鼠模型中的肿瘤消除和生存时间延长。
我们的结果表明，如何利用细胞外基质微环境中的非肿瘤内在特性来恢复免疫监视，为 HCC 免疫治疗提供了易于转化的联合策略。
