2. Academic Validation
  3. USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer

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

  • Nat Commun. 2022 Sep 26;13(1):5644. doi: 10.1038/s41467-022-33285-x.
Dongni Shi  # 1,  Xianqiu Wu  # 1 2,  Yunting Jian  # 1 3,  Junye Wang  # 4,  Chengmei Huang 1 5,  Shuang Mo 6,  Yue Li 1,  Fengtian Li 1,  Chao Zhang 7,  Dongsheng Zhang 8,  Huizhong Zhang 7,  Huilin Huang 1,  Xin Chen 9,  Y Alan Wang 10,  Chuyong Lin 1,  Guozhen Liu 11,  Libing Song 12 13,  Wenting Liao 14
Affiliations

Affiliations

  • 1 Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 510060, Guangzhou, China.
  • 2 Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
  • 3 Department of Pathology, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, 510150, Guangzhou, China.
  • 4 Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 510060, Guangzhou, China.
  • 5 Department of Pathology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China.
  • 6 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, China.
  • 7 Department of Pathology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
  • 8 Department of Medical Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
  • 9 Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Institute of Oncology, Tumor Hospital, Guangzhou Medical University, 511436, Guangzhou, China.
  • 10 Brown Center for Immunotherapy, Department of Medicine, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202-3082, USA.
  • 11 School of Life and Health Sciences, The Chinese University of Hong Kong, 518172, Shenzhen, China. liuguozhen@cuhk.edu.cn.
  • 12 Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 510060, Guangzhou, China. songlb@sysucc.org.cn.
  • 13 Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Institute of Oncology, Tumor Hospital, Guangzhou Medical University, 511436, Guangzhou, China. songlb@sysucc.org.cn.
  • 14 Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 510060, Guangzhou, China. liaowt@sysucc.org.cn.
  • # Contributed equally.
PMID: 36163134 DOI: 10.1038/s41467-022-33285-x
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.

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