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

• Published in: Nature communications Vol. 13; no. 1; pp. 5644 - 18
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/31; 13/51; 14/5; 38/1; 42/89; 631/67/2327; 64/60; 692/4028/67/1504/1885/1393; 692/4028/67/327; 82/80; Cancer; Cancer immunotherapy; Clinical trials; Colorectal cancer; Colorectal carcinoma; Cytotoxicity; Dioxygenase; Humanities and Social Sciences; Immunotherapy; Lymphocytes; Lymphocytes T; Metabolism; Microenvironments; multidisciplinary; PD-1 protein; Post-transcription; Post-translation; Proteasomes; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Therapeutic targets; Tryptophan; Tumor microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33285-x

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. IDO1-mediated tryptophan metabolism plays an important role in creating an immunosuppressive tumour microenvironment. Here, the authors show that deubiquitinase USP14 regulates immune suppression by inducing IDO1 stabilization and suggest USP14 as a potential therapeutic target to improve immunotherapy in colorectal cancer.