美国丹娜-法伯癌症研究所X. Shirley Liu、Myles Brown等研究人员合作通过体内CRISPR筛选发现E3连接酶Cop1是巨噬细胞浸润的调节因子和癌症免疫治疗的靶标。相关论文于2021年9月27日在线发表于国际学术期刊《细胞》。
通过对三阴性乳腺癌（TNBC）小鼠模型进行体内CRISPR基因敲除（KO）筛选，研究人员发现在癌细胞中敲除E3泛素连接酶Cop1会减少巨噬细胞相关趋化因子的分泌，减少肿瘤巨噬细胞浸润，增强抗肿瘤免疫力，并加强免疫检查点阻断（ICB）反应。转录组学、表观基因组学和蛋白质组学分析显示，Cop1通过蛋白体降解C/ebpδ蛋白而发挥作用。Cop1的底物Trib2是连接Cop1和C/ebpδ的支架，这导致了C/ebpδ的多聚泛素化。
此外，在癌细胞中敲除E3泛素连接酶Cop1可以稳定C/ebpδ，从而抑制巨噬细胞趋化基因的表达。这个综合方法表明，Cop1是通过调节肿瘤微环境中趋化因子的分泌和巨噬细胞的浸润来提高TNBC癌症免疫治疗效果的靶标。
据悉，尽管ICB在癌症治疗中具有显著的临床疗效，但ICB对三阴性乳腺癌（TNBC）的益处仍然有限。
附：英文原文
Title: In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target
Author: Xiaoqing Wang, Collin Tokheim, Shengqing Stan 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 Long, Myles Brown, X. Shirley Liu
Issue&Volume: 2021-09-27
Abstract: Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancertreatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Throughpooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletionof the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reducestumor 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 approachimplicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokinesecretion and macrophage infiltration in the tumor microenvironment.
DOI: 10.1016/j.cell.2021.09.006
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01053-9