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

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

doi:10.1016/j.apsb.2023.08.014

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

Acta Pharm Sin B. 2024 Feb;14(2):854-868. doi: 10.1016/j.apsb.2023.08.014. Epub 2023 Aug 19.

Authors

Yunzhu Lin^{1

2}, Xiang Wang³, Shi He³, Zhongxin Duan³, Yunchu Zhang³, Xiaodong Sun⁴, Yuzhu Hu⁵, Yuanyuan Zhang¹, Zhiyong Qian³, Xiang Gao³, Zhirong Zhang¹

Affiliations

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 West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China.
⁵ 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.

Abstract

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 (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 microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

Keywords: Checkpoint blocker; IL-12 encoding gene; Immune escape; Immunotherapy; Nanoparticles; Ovarian cancer; Targeted delivery; Tumor microenvironment.