Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

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外文摘要：Immune evasion has made ovarian cancer notorious for its refractory features,making the development of immunotherapy highly appealing to ovarian cancer treatment.The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities.However,IL-12 can induce IFN-y release and sub-sequently upregulate PDL-1 expression on tumor cells.Therefore,the tumor-targeting folate-modified de-livery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(iPDL-1)to reduce immune escape and boost anti-tumor immunity.The physicochemical characteristics,gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed.The immune-modulation effects of combination therapy on different immune cells are also studied.Results show that compared with non-folate-modified vector,folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12.The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation,NK activation,macrophage polarization and DC maturation.The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice.Taken together,our work provides new insights into ovarian cancer immunotherapy.Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune micro-environment and preventing immune escape and might be a promising treatment option for ovarian can-cer treatment.

外文关键词：

IL-12 encoding geneCheckpoint blockerNanoparticlesTargeted deliveryTumor microenvironmentImmune escapeOvarian cancerImmunotherapy

作者：

Yunzhu Lin、Xiang Wang、Shi He、Zhongxin Duan、Yunchu Zhang、Xiaodong Sun、Yuzhu Hu、Yuanyuan Zhang、Zhiyong Qian、Xiang Gao、Zhirong Zhang

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作者单位：

Key Laboratory of Drug Targeting and Drug Delivery Systems,Ministry of Education,West China School of Pharmacy,Sichuan University,Chengdu 610041,China

Department of Pharmacy,Evidence-based Pharmacy Center,West China Second University Hospital,Key Laboratory of Birth Defects and Related Diseases of Women and Children,Sichuan University,Chengdu 610041,China

Department of Neurosurgery and Institute of Neurosurgery,State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,West China Medical School,Sichuan University and Collaborative Innovation Center for Biotherapy,Chengdu 610041,China

West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University,Chengdu 610041,China

Department of Radiation Oncology,State Key Laboratory of Biotherapy and Cancer Center

West China Hospital,West China Medical School,Sichuan University and Collaborative Innovation Center for Biotherapy,Chengdu 610041,China

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基金：

National Natural Science Foundation of China,ChinaNational Natural Science Foundation of China,ChinaNational Natural Science Foundation of China,ChinaNational Natural Science Foundation of China,ChinaSichuan Science and Technology Program,ChinaSichuan Science and Technology Program,China1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University,China

项目编号：

322220468217263082170844822706132022YFH00452022YFH0102ZYJC21022

出版年：

2024

DOI：

10.1016/j.apsb.2023.08.014

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(2)

参考文献量54