RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
鸦胆子油乳剂显著提高了抗 PD-1 免疫治疗的疗效
英文原题：Brucea javanica oil emulsion significantly improved the effect of anti-programmed cell death protein-1 immunotherapy.
查看英文原题
Brucea javanica oil emulsion significantly improved the effect of anti-programmed cell death protein-1 immunotherapy.
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研究概要
我们的工作探索了市售 BJOE 的抗肿瘤机制以及 BJOE 体内联合 anti-PD-1 治疗时对细胞因子的调控。这些疗法的联合可增加肿瘤组织中 CD4 + T 细胞、CD8 + T 细胞和有效 NK 细胞的数量以及 MI/M2 巨噬细胞的比例，促进炎症活性并增强抗肿瘤效果。本研究为推进中药制剂的现代发展提供了理论依据，并为临床提高 PD-1 抗体疗效提供了参考。
研究思路结论见上方概要
背景
鸦胆子油（BJO）是从鸦胆子干燥成熟果实中提取的活性物质。其药物制剂鸦胆子油乳剂（BJOE）是研究最广泛的中药抗恶性肿瘤制剂之一。然而，其抗肿瘤机制尚未阐明，极大限制了BJOE的进一步开发。
目的
在本研究中，我们深入探讨了市售BJOE的抗肿瘤机制，包括其对肿瘤微环境（TME）的影响以及与抗程序性细胞死亡蛋白-1（PD-1）疗法联合使用时的治疗效果。
方法
BJOE的细胞毒性在体外不同细胞中进行了测试，并构建了Förster共振能量转移系统以预测BJOE在体内的释放行为。随后，采用B16黑色素瘤小鼠模型探究BJOE与抗小鼠PD-1抗体联合治疗的效果。此外，利用质谱流式技术检测了两种药物对TME的影响。
结果
我们的数据表明，BJOE在体外并不直接杀死肿瘤细胞。然而，BJOE主要在肿瘤部位释放，将免疫抑制性TME转化为免疫激活状态，并且其与anti-PD-1疗法联合显著抑制了黑色素瘤的生长并延长了小鼠的生存时间，这是由于淋巴结和肿瘤中细胞毒性T淋巴（CD8 + T）和辅助/诱导性T淋巴（CD4 + T）细胞增加所致。
展开英文摘要原文
BACKGROUND
Brucea javanica oil (BJO) is the active substance extracted from the dry and mature fruit of Brucea javanica. Its pharmaceutical preparation, BJO emulsion (BJOE), is one of the most widely studied traditional Chinese medicine preparations for the treatment of malignancy. However, the unrevealed anti-tumor mechanism immensely limits further development of BJOE.
PURPOSE
In this study, we delved into the anti-tumor mechanism of commercial BJOE, including its influence on the tumor microenvironment (TME) and the treatment effect when combined with anti-programmed cell death protein-1 (PD-1) therapy.
METHODS
The cytotoxicity of BJOE was tested in different cells in vitro, and a Förster resonance energy transfer system was also constructed to predict the release behavior of BJOE in vivo. Then, a B16 melanoma mouse model was used to explore the combination of BJOE and anti-mouse PD-1 antibody therapy. In addition, mass cytometry was used to test the impact of both drugs on the TME.
RESULTS
Out data revealed that BJOE did not directly kill tumor cells in vitro. However, BJOE was mainly released at the tumor site, converting an immunosuppressive TME into an immune-activated state, and its combination with anti-PD-1 therapy significantly inhibited the growth of melanoma and prolonged the survival time of the mice due to an increase in cytotoxic T lymph (CD8 + T) and helper/inducible T lymph (CD4 + T) cells in lymph nodes and tumors.
CONCLUSIONS
Our work explored the anti-tumor mechanism of commercial BJOE and the regulation of cytokines by BJOE when it was combined with anti-PD-1 therapy in vivo. The combination of these therapies could increase the numbers of CD4 + T-cells, CD8 + T-cells, and effective natural killer cells and the ratio of MI/M2 macrophages in tumor tissues, promoting inflammatory activity and enhancing the anti-tumor effect. This study provides a theoretical basis for advancing the modern development of traditional Chinese medicine preparations and stands as a reference for clinically improving the efficacy of PD-1 antibodies.
论文信息
- 作者
- Meng J、Yu Z、Chen H、Yu X、Jiang M、Zeng XA、You J
- 第一作者单位
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510641, China.China
- 通讯作者单位
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China. Electronic address: youjiandoc@zju.edu.cn.China
- 期刊
- Phytomedicine : international journal of phytotherapy and phytopharmacology2022 Dec
- 原文标识
- PubMed 36182799 · DOI 10.1016/j.phymed.2022.154446