https://scholars.lib.ntu.edu.tw/handle/123456789/640187
標題: | Codelivery of TGFβ and Cox2 siRNA inhibits HCC by promoting T-cell penetration into the tumor and improves response to Immune Checkpoint Inhibitors | 作者: | Kim, Wookhyun Ye, Zhou Simonenko, Vera Shahi, Aashirwad Malikzay, Asra Long, Steven Z Xu, John J Lu, Alan Horng, Jau-Hau Wu, Chang-Ru PEI-JER CHEN Lu, Patrick Y Evans, David M |
公開日期: | 三月-2024 | 卷: | 6 | 期: | 1 | 來源出版物: | NAR cancer | 摘要: | Upregulation of TGFβ and Cox2 in the tumor microenvironment results in blockade of T-cell penetration into the tumor. Without access to tumor antigens, the T-cell response will not benefit from administration of the immune checkpoint antibodies. We created an intravenous polypeptide nanoparticle that can deliver two siRNAs (silencing TGFβ and Cox2). Systemic administration in mice, bearing a syngeneic orthotopic hepatocellular carcinoma (HCC), delivers the siRNAs to various cells in the liver, and significantly reduces the tumor. At 2 mg/kg (BIW) the nanoparticle demonstrated a single agent action and induced tumor growth inhibition to undetectable levels after five doses. Reducing the siRNAs to 1mg/kg BIW demonstrated greater inhibition in the presence of PD-L1 mAbs. After only three doses BIW, we could still recover a smaller tumor and, in tumor sections, showed an increase in penetration of CD4+ and CD8+ T-cells deeper into the remaining tumor that was not evident in animals treated with non-silencing siRNA. The combination of TGFβ and Cox2 siRNA co-administered in a polypeptide nanoparticle can act as a novel therapeutic alone against HCC and may augment the activity of the immune checkpoint antibodies. Silencing TGFβ and Cox2 converts an immune excluded (cold) tumor into a T-cell inflamed (hot) tumor. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/640187 | ISSN: | 2632-8674 | DOI: | 10.1093/narcan/zcad059 |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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