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- Title
siRNA Nanoparticle Targeting PD-L1 Activates Tumor Immunity and Abrogates Pancreatic Cancer Growth in Humanized Preclinical Model.
- Authors
Jung, Jae Yun; Ryu, Hyun Jin; Lee, Seung-Hwan; Kim, Dong-Young; Kim, Myung Ji; Lee, Eun Ji; Ryu, Yeon-Mi; Kim, Sang-Yeob; Kim, Kyu-Pyo; Choi, Eun Young; Ahn, Hyung Jun; Chang, Suhwan
- Abstract
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.
- Subjects
NUCLEAR Suppliers Group (Company); PANCREATIC cancer; TUMOR growth; PROGRAMMED death-ligand 1; ANIMAL models in research; SMALL interfering RNA; CYTOTOXIC T cells; T cells
- Publication
Cells (2073-4409), 2021, Vol 10, Issue 10, p2734
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells10102734