| First Author | Zhang X | Year | 2021 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 12 |
| Issue | 4 | Pages | 1179-1199 |
| PubMed ID | 34087454 | Mgi Jnum | J:312886 |
| Mgi Id | MGI:6793647 | Doi | 10.1016/j.jcmgh.2021.05.018 |
| Citation | Zhang X, et al. (2021) Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune Tolerance. Cell Mol Gastroenterol Hepatol 12(4):1179-1199 |
| abstractText | 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. |
