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Camptothesome elicits immunogenic cell death to boost colorectal cancer immune checkpoint blockade
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2022-08-09 , DOI: 10.1016/j.jconrel.2022.07.042
Zhiren Wang 1 , Wenpan Li 1 , Jonghan Park 1 , Karina Marie Gonzalez 1 , Aaron James Scott 2 , Jianqin Lu 3
Affiliation  

Camptothesome is an innovative nanovesicle therapeutic comprising the sphingomyelin-derived camptothecin (CPT) lipid bilayer. In this work, we deciphered that Camptothesome was taken up by colorectal cancer (CRC) cells through primarily the clathrin-mediated endocytotic pathway and displayed the potential of eliciting robust immunogenic cancer cell death (ICD) via upregulating calreticulin, high mobility group box 1 protein (HMGB-1), and adenosine triphosphate (ATP), three hallmarks involved in the induction of ICD. In addition, use of dying MC38 tumor cells treated with Camptothesome as vaccine prevented tumor growth in 60% mice that received subsequent injection of live MC38 cells on the contralateral flank, validating Camptothesome was a legitimate ICD inducer in vivo. Camptothesome markedly reduced the acute bone marrow toxicity and gastrointestinal mucositis associated with free CPT and beat free CPT and Onivyde on anti-CRC efficacy and immune responses in a partially interferon gamma (IFN-γ)-dependent manner. Furthermore, Camptothesome enhanced the efficacy of immune checkpoint inhibitors to shrink late-stage orthotopic MC38 CRC tumors with diminished tumor metastasis and markedly prolonged mice survival.



中文翻译:

Camptothesome 引发免疫原性细胞死亡以增强结直肠癌免疫检查点封锁

Camptothesome 是一种创新的纳米囊泡治疗剂,包含鞘磷脂衍生的喜树碱 (CPT) 脂质双层。在这项工作中,我们破译了 Camptothesome 主要通过网格蛋白介导的内吞途径被结肠直肠癌 (CRC) 细胞吸收,并显示出通过上调钙网蛋白、高迁移率组框 1 蛋白引发强大的免疫原性癌细胞死亡 (ICD) 的潜力(HMGB-1) 和三磷酸腺苷 (ATP),这三个标志参与了 ICD 的诱导。此外,使用经 Camptothesome 处理的垂死 MC38 肿瘤细胞作为疫苗阻止了 60% 小鼠的肿瘤生长,这些小鼠随后在对侧侧腹注射了活的 MC38 细胞,证实 Camptothesome 在体内是一种合法的 ICD 诱导剂。Camptothesome 显着降低了与游离 CPT 相关的急性骨髓毒性和胃肠道粘膜炎,并以部分干扰素 γ (IFN-γ) 依赖的方式击败了游离 CPT 和 Onivyde 对抗 CRC 功效和免疫反应的影响。此外,Camptothesome 增强了免疫检查点抑制剂缩小晚期原位 MC38 CRC 肿瘤的功效,同时减少了肿瘤转移并显着延长了小鼠的存活时间。

更新日期:2022-08-09
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