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

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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.
Author(s)
김규표김동영김명지김상엽류연미류현진이승환이은지정재윤최은영안형준장수환
Issued Date
2021
Type
Article
Keyword
siRNA nanoparticle pancreatic cancer PD-L1 immunotherapy humanized NSG
DOI
10.3390/cells10102734
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7538
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_82d23eafc789421396a56d1cad893624&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,siRNA%20Nanoparticle%20Targeting%20PD-L1%20Activates%20Tumor%20Immunity%20and%20Abrogates%20Pancreatic%20Cancer%20Growth%20in%20Humanized%20Preclinical%20Model&offset=0&pcAvailability=true
Publisher
CELLS
Location
미국
Language
영어
ISSN
2073-4409
Citation Volume
10
Citation Number
10
Citation Start Page
0
Citation End Page
0
Appears in Collections:
Medicine > Medicine
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