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

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

作者机构：Key Laboratory of Drug Targeting and Drug Delivery SystemsMinistry of EducationWest China School of PharmacySichuan UniversityChengdu 610041China Department of PharmacyEvidence-based Pharmacy CenterWest China Second University HospitalKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenSichuan UniversityChengdu 610041China Department of Neurosurgery and Institute of NeurosurgeryState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Radiation OncologyState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China West China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityChengdu 610041China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2024年第14卷第2期

页      面：854-868页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(Nos.32222046,82172630,82170844 and 82270613,China) the Sichuan Science and Technology Program(Nos.2022YFH0045 and 2022YFH0102,China) the 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYJC21022,China) 

主　　题：IL-12encodinggene Checkpointblocker Nanoparticles Targeted delivery Tumormicroenvironment Immune escape Ovarian cancer Immunotherapy 

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-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(i PDL-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 p IL-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/p IL-12/i PDL-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/p IL-12/i PDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.