泛素连接酶
生物
癌症研究
癌症免疫疗法
肿瘤微环境
免疫检查点
趋化因子
免疫疗法
泛素
细胞生物学
免疫系统
免疫学
生物化学
基因
作者
Xiaoqing Wang,Collin Tokheim,Shengqing Gu,Binbin Wang,Qin Tang,Yihao Li,Nicole Traugh,Zexian Zeng,Yi Zhang,Ziyi Li,Boning Zhang,Jingxin Fu,Tengfei Xiao,Wei Li,Clifford A. Meyer,Jun Chu,Peng Jiang,Paloma Cejas,Klothilda Lim,Henry W. Long,Myles Brown,X. Shirley Liu
出处
期刊:Cell
[Elsevier]
日期:2021-09-27
卷期号:184 (21): 5357-5374.e22
被引量:106
标识
DOI:10.1016/j.cell.2021.09.006
摘要
Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment.
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