Journal
CELLS
Volume 10, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/cells10102734
Keywords
siRNA; nanoparticle; pancreatic cancer; PD-L1; immunotherapy; humanized NSG
Categories
Funding
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)
- Ministry of Health and Welfare, Republic of Korea [HR21C0198030021]
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Education [2021R1A6A1A0304026011]
- Asan Institute for Life Sciences [2020IL0042-1]
- KIST institutional Program [2E31091]
- Korea Health Promotion Institute [HR21C0198030021] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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siPD-L1@PLGA nanoparticles efficiently target PD-L1 in pancreatic cancer cells, enhancing sensitivity to antigen-specific immune cells.
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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