交通2
髓系白血病
癌症研究
免疫系统
下调和上调
信号转导衔接蛋白
信号转导
细胞生物学
NF-κB
白血病
生物
免疫检查点
免疫学
细胞因子
免疫疗法
基因
肿瘤坏死因子受体
生物化学
作者
Guojin Wu,Yixiang Xu,Robbie D. Schultz,Heyu Chen,Jingjing Xie,Mi Deng,Xiaoye Liu,Xun Gui,Samuel John,Zhigang Lu,Hisashi Arase,Ningyan Zhang,Zhiqiang An,Cheng Zhang
出处
期刊:Nature cancer
[Springer Nature]
日期:2021-11-11
卷期号:2 (11): 1170-1184
被引量:26
标识
DOI:10.1038/s43018-021-00262-0
摘要
Leukocyte immunoglobulin-like receptor B (LILRB), a family of immune checkpoint receptors, contributes to acute myeloid leukemia (AML) development, but the specific mechanisms triggered by activation or inhibition of these immune checkpoints in cancer is largely unknown. Here we demonstrate that the intracellular domain of LILRB3 is constitutively associated with the adaptor protein TRAF2. Activated LILRB3 in AML cells leads to recruitment of cFLIP and subsequent NF-κB upregulation, resulting in enhanced leukemic cell survival and inhibition of T-cell-mediated anti-tumor activity. Hyperactivation of NF-κB induces a negative regulatory feedback loop mediated by A20, which disrupts the interaction of LILRB3 and TRAF2; consequently the SHP-1/2-mediated inhibitory activity of LILRB3 becomes dominant. Finally, we show that blockade of LILRB3 signaling with antagonizing antibodies hampers AML progression. LILRB3 thus exerts context-dependent activating and inhibitory functions, and targeting LILRB3 may become a potential therapeutic strategy for AML treatment.
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