Interventional Radiology Center, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong, China
Interventional Radiology Center, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong, China.
Gut. 2022 Dec;71(12):2551-2560. doi: 10.1136/gutjnl-2021-326350. Epub 2022 Feb 16.
Patients with increased PD-L1 host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1 host cells in hepatocellular carcinoma (HCC).
A total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1 cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies.
We demonstrate that PD-L1 host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRCD86 glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2 glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties.
Selectively modulating the 'context' of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy.
肿瘤中 PD-L1 宿主细胞增加的患者更能从抗程序性死亡-1/程序性死亡配体-1（PD-L1）治疗中获益，但潜在机制仍不清楚。我们旨在阐明 PD-L1 宿主细胞在肝细胞癌（HCC）中的性质、调控和功能相关性。
共纳入 184 例未经治疗的 HCC 患者进行随机分组。C57BL/6 小鼠给予 Hepa1-6 细胞注射以形成自体肝癌。应用 ELISpot、流式细胞术和实时 PCR 分析直接从 HCC 标本分离的 PD-L1 细胞的表型特征，这些标本与血液样本配对，或从离体和体外培养系统中获得。免疫荧光和免疫组化用于检测石蜡包埋和福尔马林固定样本中免疫细胞的存在。通过体外和体内研究评估代谢转换的潜在调控机制。
我们证明 PD-L1 宿主巨噬细胞在 HCC 肿瘤中构成 PD-L1 的主要细胞来源，表现出 HLA-DRCD86 糖酵解表型，显著产生抗肿瘤 IL-12p70，并通过内在糖酵解代谢极化。从机制上讲，肝癌细胞衍生的纤连蛋白 1 通过 HIF-1α依赖性方式触发的关键糖酵解酶 PKM2 ，同时控制糖酵解巨噬细胞的抗肿瘤特性和炎症介导的 PD-L1 表达。重要的是，尽管增加的 PKM2 糖酵解巨噬细胞预示着患者预后不良，但阻断这些细胞上的 PD-L1 消除了 PD-L1 主导的免疫抑制作用，并释放了内在的抗肿瘤特性。
选择性调节 HCC 肿瘤中糖酵解巨噬细胞的“环境”可能恢复其抗肿瘤特性，并为癌症治疗提供精确策略。
