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 

机构地区：[1]Key Laboratory of Drug Targeting and Drug Delivery Systems,Ministry of Education,West China School of Pharmacy,Sichuan University,Chengdu 610041,China [2]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 [3]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 [4]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 [5]West China School of Basic Medical Sciences&Forensic Medicine,Sichuan University,Chengdu 610041,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第2期854-868,共15页药学学报（英文版）

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).

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.

关 键 词：IL-12encodinggene Checkpointblocker Nanoparticles Targeted delivery Tumormicroenvironment Immune escape Ovarian cancer IMMUNOTHERAPY 

分 类 号：R737.31[医药卫生—肿瘤]