USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer

作者：Shi, Dongni; Wu, Xianqiu; Jian, Yunting; Wang, Junye; Huang, Chengmei; Mo, Shuang; Li, Yue; Li, Fengtian; Zhang, Chao; Zhang, Dongsheng; Zhang, Huizhong; Huang, Huilin; Chen, Xin; Wang, Y. Alan; Lin, Chuyong; Liu, Guozhen^*; Song, Libing^*; Liao, Wenting^*

来源：Nature Communications, 2022, 13(1): 5644.

DOI：10.1038/s41467-022-33285-x

• INDOLEAMINE 2,3-DIOXYGENASE
• T-CELL
• TUMOR PROGRESSION
• PROLIFERATION
• INHIBITION
• EXPRESSION
• DEGRADATION
• ACTIVATION
• RESISTANCE
• PATHWAY

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.

• 单位
  广州医学院; 南方医科大学; 中山大学