TGFβ和Cox2 siRNA联合递送可通过促进T细胞穿透肿瘤抑制HCC,并改善对免疫检查点抑制剂的反应。

IF 3.4 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
NAR cancer Pub Date : 2024-01-09 eCollection Date: 2024-03-01 DOI:10.1093/narcan/zcad059
Wookhyun Kim, Zhou Ye, Vera Simonenko, Aashirwad Shahi, Asra Malikzay, Steven Z Long, John J Xu, Alan Lu, Jau-Hau Horng, Chang-Ru Wu, Pei-Jer Chen, Patrick Y Lu, David M Evans
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引用次数: 0

摘要

肿瘤微环境中 TGFβ 和 Cox2 的上调会阻碍 T 细胞进入肿瘤。如果无法进入肿瘤抗原,T细胞反应就无法从免疫检查点抗体的给药中获益。我们创造了一种静脉注射多肽纳米粒子,它能递送两种 siRNA(沉默 TGFβ 和 Cox2)。在小鼠体内全身给药,将 siRNAs 运送到肝脏中的各种细胞,可显著减少肿瘤。2毫克/千克(白蛋白)的纳米颗粒显示出单剂作用,并在五次剂量后将肿瘤生长抑制到检测不到的水平。在PD-L1 mAbs存在的情况下,将siRNA降至1毫克/千克BIW的抑制作用更大。在只服用三剂 BIW 后,我们仍能恢复较小的肿瘤,并且在肿瘤切片中显示,CD4+ 和 CD8+ T 细胞渗透到剩余肿瘤的更深部位,这在使用非沉默 siRNA 的动物中并不明显。将TGFβ和Cox2 siRNA结合在多肽纳米颗粒中共同给药,可作为一种新的治疗方法单独对抗HCC,并可增强免疫检查点抗体的活性。沉默 TGFβ 和 Cox2 可将免疫排斥(冷)肿瘤转化为 T 细胞炎症(热)肿瘤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Codelivery of TGFβ and Cox2 siRNA inhibits HCC by promoting T-cell penetration into the tumor and improves response to Immune Checkpoint Inhibitors.

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.

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CiteScore
6.90
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