为肝细胞癌武装 GPC3 CAR-T 细胞：多少才足够，下一步是什么？
Armouring GPC3 CAR T cells for hepatocellular carcinoma: how much is enough and what comes next?
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
丹参酮 IIA 通过抑制 ELTD1 使肝细胞癌血管正常化并增强 PD-1 抑制剂疗效
英文原题：Tanshinone IIA normalized hepatocellular carcinoma vessels and enhanced PD-1 inhibitor efficacy by inhibiting ELTD1.
查看英文原题
Tanshinone IIA normalized hepatocellular carcinoma vessels and enhanced PD-1 inhibitor efficacy by inhibiting ELTD1.
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研究概要
本研究揭示了 TSA 与 ELTD1 之间促进血管正常化的新机制，提示针对 ELTD1 的治疗或药理干预可能增强 PD-1 抑制剂在 HCC 中的疗效。
研究思路结论见上方概要
背景
肝细胞癌对免疫检查点抑制剂（如 PD-1 抑制剂）反应不佳，主要原因是 TILs 在 TME 中的浸润能力低。异常血管是限制 TILs 浸润的重要因素。根据近期研究，靶向 ELTD1 表达可能改善 TILs 的递送，从而逆转免疫抑制并增强肿瘤对免疫治疗的应答。研究已证明丹参酮 IIA（TSA）可改善血管正常化，但具体机制尚不清楚。
目的
本研究的目的是在体外和体内探讨TSA促进HCC血管正常化的分子过程。
方法
我们建立了小鼠H22-luc原位肝癌模型，以评估TSA血管正常化和免疫抑制微环境的作用。通过TCGA数据库的生物信息学分析，评估了ELTD1在血管和免疫串扰中的作用。通过创建transwell共培养细胞模型，评估了TSA对增强肿瘤内皮细胞活性的影响以及ELTD1干预的效果。
结果
我们研究了丹参酮IIA（TSA），丹参的主要成分，对原位HCC模型血管正常化的影响。我们的结果表明，TSA在原位肝细胞癌模型中诱导了血管正常化。此外，TSA与抗PD-1联合使用由于肿瘤中免疫细胞浸润增加而显著抑制了肿瘤发展。在机制上，我们证明TSA通过抑制ELTD1表达、抑制下游JAK1和JAK2、促进ZO-1、occlaudin、Claudin 5和Col IV的表达，以及促进原位血管完整性和灌注，从而抑制肿瘤生长，改善了免疫抑制微环境。
展开英文摘要原文
BACKGROUND
Hepatocellular carcinoma responds poorly to immune checkpoint inhibitors, such as PD-1 inhibitors, primarily due to the low infiltration capacity of TILs in the TME. Abnormal vasculature is an important factor which limiting the infiltration of TILs. According to recent research, targeting ELTD1 expression may improve TILs delivery to reverse immunosuppression and boost tumor responses to immunotherapy. Research has demonstrated that Tanshinone IIA (TSA) improves blood vessel normalization, but the precise mechanism is yet unknown.
PURPOSE
The purpose of this study is to investigate the molecular processes for TSA's pro-vascular normalization of HCC in vitro and in vivo.
METHODS
We established a mouse H22-luc in situ liver tumor model to evaluate the role of TSA vascular normalization and the immunosuppressive microenvironment. The role of ELTD1 in vascular and immune crosstalk was evaluated by bioinformatic analysis of the TCGA database. By creating a transwell co-culture cell model, the effects of TSA on enhancing tumor endothelial cell activities and ELTD1 intervention were evaluated.
RESULTS
We investigated the effect of Tanshinone IIA (TSA), a major component of Salvia miltiorrhiza Bge., on the normalization of vasculature in situ HCC models. Our results demonstrated that TSA elicited vascular normalization in a hepatocellular carcinoma model in situ. In addition, the combination of TSA with anti-PD-1 significantly inhibited tumor development due to increased infiltration of immune cells in the tumor. Mechanistically, we demonstrated that TSA improved the immunosuppressive microenvironment by inhibiting tumor growth by suppressing ELTD1 expression, inhibiting downstream JAK1 and JAK2, promoting the expression of ZO-1, occlaudin, Claudin 5, and Col IV, and promoting vascular integrity and perfusion in situ.
CONCLUSIONS
This study reveals a new mechanism between TSA and ELTD1 for vascular normalization, suggesting that therapeutic or pharmacological intervention with ELTD1 may enhance the efficacy of PD-1 inhibitors in HCC.
论文信息
- 作者
- Mao D、Wang H、Guo H、Che X、Chen M、Li X、Liu Y、Huo J
- 第一作者单位
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 210023 Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.China
- 通讯作者单位
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 210023 Nanjing, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China; Jiangsu Clinical Innovation Center of Digestive Cancer of Traditional Chinese Medicine Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing, China. Electronic address: chenyan@jsatcm.com.China
- 期刊
- Phytomedicine : international journal of phytotherapy and phytopharmacology2024 Jan
- 原文标识
- PubMed 38000104 · DOI 10.1016/j.phymed.2023.155191