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

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, Y. Alan Wang, Chuyong Lin, Guozhen Liu (), Libing Song () and Wenting Liao ()
Additional contact information
Dongni Shi: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Xianqiu Wu: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Yunting Jian: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Junye Wang: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Chengmei Huang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Shuang Mo: Sun Yat-sen University
Yue Li: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Fengtian Li: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Chao Zhang: Sun Yat-sen University Cancer Center
Dongsheng Zhang: Sun Yat-sen University Cancer Center
Huizhong Zhang: Sun Yat-sen University Cancer Center
Huilin Huang: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Xin Chen: Guangzhou Medical University
Y. Alan Wang: Indiana University School of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center
Chuyong Lin: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Guozhen Liu: The Chinese University of Hong Kong
Libing Song: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Wenting Liao: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-33285-x

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