二硫仑
免疫原性细胞死亡
CD47型
钙网蛋白
癌症研究
封锁
免疫系统
化学
程序性细胞死亡
免疫检查点
细胞凋亡
药理学
医学
内质网
免疫学
免疫疗法
受体
生物化学
作者
Xingxing Gao,Hechen Huang,Caixu Pan,Zhibin Mei,Shengyong Yin,Lin Zhou,Shusen Zheng
出处
期刊:Cancers
[MDPI AG]
日期:2022-09-28
卷期号:14 (19): 4715-4715
标识
DOI:10.3390/cancers14194715
摘要
Some chemotherapeutic agents have been found to enhance antitumor immunity by inducing immunogenic cell death (ICD). The combination of disulfiram (DSF) and copper (Cu) has demonstrated anti-tumor effects in a range of malignancies including hepatocellular carcinoma (HCC). However, the potential of DSF/Cu as an ICD inducer and whether it can enhance the efficacy of the immune checkpoint blockade in HCC remains unknown. Here, we showed that DSF/Cu-treated HCC cells exhibited characteristics of ICD in vitro, such as calreticulin (CRT) exposure, ATP secretion, and high mobility group box 1 (HMGB1) release. DSF/Cu-treated HCC cells elicited significant immune memory in a vaccination assay. DSF/Cu treatment promoted dendritic cell activation and maturation. The combination of DSF/Cu and CD47 blockade further facilitated DC maturation and subsequently enhanced CD8+ T cell cytotoxicity. Mechanically, DSF/Cu promoted the nuclear accumulation and aggregation of nuclear protein localization protein 4 (NPL4) to inhibit the ubiquitin-proteasome system; thus, inducing endoplasmic reticulum (ER) stress. The inhibition of NPL4 induced ICD-associated damage-associated molecular patterns. Collectively, our findings demonstrated that DSF/Cu-induced ICD-mediated immune activation in HCC enhanced the efficacy of CD47 blockade.
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