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siRNA Nanoparticle Targeting PD-L1 Activates Tumor Immunity and Abrogates Pancreatic Cancer Growth in Humanized Preclinical Model

Jae Yun JungDepartment of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, KoreaHyun Jin RyuDepartment of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, KoreaSeung‐Hwan LeeUniversity of UlsanDong‐Young KimDepartment of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, KoreaMyung Ji KimDepartment of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, KoreaEun Ji LeeDepartment of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, KoreaYeon‐Mi RyuAsan Medical Center, Asan Institute for Life Sciences, Seoul 05505, KoreaSang‐Yeob KimAsan Medical Center, Asan Institute for Life Sciences, Seoul 05505, KoreaKyu‐pyo KimAsan Medical Center, Department of Oncology, Seoul 05505, KoreaEun Young ChoiDepartment of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, KoreaHyung Jun AhnCenter for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 05505, KoreaSuhwan ChangDepartment of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea

2021en

ABI

Annotatsiya

Pancreatic cancer is characterized by late detection, frequent drug resistance, and a highly metastatic nature, leading to poor prognosis. Antibody-based immunotherapy showed limited success for pancreatic cancer, partly owing to the low delivery rate of the drug into the tumor. Herein, we describe a poly(lactic-co-glycolic acid;PLGA)-based siRNA nanoparticle targeting PD-L1 (siPD-L1@PLGA). The siPD-L1@PLGA exhibited efficient knockdown of PD-L1 in cancer cells, without affecting the cell viability up to 6 mg/mL. Further, 99.2% of PDAC cells uptake the nanoparticle and successfully blocked the IFN-gamma-mediated PD-L1 induction. Consistently, the siPD-L1@PLGA sensitized cancer cells to antigen-specific immune cells, as exemplified by Ovalbumin-targeting T cells. To evaluate its efficacy in vivo, we adopted a pancreatic PDX model in humanized mice, generated by grafting CD34+ hematopoeitic stem cells onto NSG mice. The siPD-L1@PLGA significantly suppressed pancreatic tumor growth in this model with upregulated IFN-gamma positive CD8 T cells, leading to more apoptotic tumor cells. Multiplex immunofluorescence analysis exhibited comparable immune cell compositions in control and siPD-L1@PLGA-treated tumors. However, we found higher Granzyme B expression in the siPD-L1@PLGA-treated tumors, suggesting higher activity of NK or cytotoxic T cells. Based on these results, we propose the application of siPD-L1@PLGA as an immunotherapeutic agent for pancreatic cancer.

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Identifikatorlar

DOI: 10.3390/cells10102734

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