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

Xin Zhang, Xiuting Liu, Wei Zhou, Qianming Du, Mengdi Yang, Yang Ding, Rong Hu

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1179-1199
Number of pages21
JournalCMGH
Volume12
Issue number4
DOIs
StatePublished - Jan 2021

Keywords

  • AhR
  • Colitis-Associated Colon Cancer
  • IDO
  • Kyn
  • Treg

Fingerprint

Dive into the research topics of 'Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune Tolerance'. Together they form a unique fingerprint.

Cite this