Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune ToleranceSummary

Cellular and Molecular Gastroenterology and Hepatology

Mengdi Yang¹  Rong Hu²  Xiuting Liu³  Yang Ding⁴  Xin Zhang⁵  Qianming Du⁵  Wei Zhou⁵ 

[1] Department of Children Health Care, Children’s Hospital of Nanjing Medical University, Nanjing, China;General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China;State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China;General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China;State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China;

关键词: IDO;    Kyn;    AhR;    Treg;    Colitis-Associated Colon Cancer;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background & Aims: Chronic inflammation in colon section is associated with an increased risk of colorectal cancer (CRC). Proinflammatory cytokines were produced in a tumor microenvironment and correlated with poor clinical outcome. Tumor-infiltrating T cells were reported to be greatly involved in the development of colon cancer. In this study, we demonstrated that kynurenine (Kyn), a metabolite catalyzed by indoleamine 2,3-dioxygenase (IDO), was required for IDO-mediated T cell function, and adaptive immunity indeed played a critical role in CRC. Methods: Supernatant of colon cancer cells was used to culture activated T cells and mice spleen lymphocytes, and the IDO1-Kyn-aryl hydrocarbon (AhR) receptor axis was determined in vitro. In vivo, an azoxymethane (AOM)/dextran sodium sulfate (DSS)–induced CRC model was established in IDO–/–, Rag1–/–, and wild-type mice, and tumor-associated T lymphocyte infiltration and Kyn/AhR signaling pathway changes were measured in each group. Results: Kyn promoted AhR nuclear translocation increased the transcription of Foxp3, a marker of regulatory T cells (Tregs), through improving the interaction between AhR and Foxp3 promoter. Additionally, compared WT mice, IDO–/– mice treated with AOM/DSS exhibited fewer and smaller tumor burdens in the colon, with less Treg and more CD8+ T cells infiltration, while Kyn administration abolished this regulation. Rag1–/– mice were more sensitive to AOM/DSS-induced colitis-associated colon cancer (CRC) compared with the wild-type mice, suggesting that T cell–mediated adaptive immunity indeed played a critical role in CRC. Conclusions: We demonstrated that inhibition of IDO diminished Kyn/AhR-mediated Treg differentiation and could be an effective strategy for the prevention and treatment of inflammation-related colon cancer.

【 授权许可】

Unknown