脱氮酶
癌症研究
结直肠癌
免疫系统
癌症
癌症免疫疗法
免疫疗法
生物
基因敲除
免疫
免疫学
泛素
基因
生物化学
遗传学
作者
Dongni Shi,Xianqiu Wu,Yunting Jian,Junye Wang,Chengmei Huang,Shuang Mo,Yue Li,Fengtian Li,Chao Zhang,Dongsheng Zhang,Huizhong Zhang,Huilin Huang,Xin Chen,Yue Wang,Chuyong Lin,Guozhen Liu,Libing Song,Wenting Liao
标识
DOI:10.1038/s41467-022-33285-x
摘要
Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy.
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