Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune Tolerance.
Blockade of IDO-Kynurenine-AhR Axis Ameliorated Colitis-Associated Colon Cancer via Inhibiting Immune Tolerance.
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阻断 IDO-Kynurenine-AhR 轴可通过抑制免疫耐受改善结肠炎相关结肠癌
DOI：
10.1016/j.jcmgh.2021.05.018
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发表时间：
2021
影响因子：
7.2
通讯作者：
Hu R
中科院分区：
文献类型：
--
作者：
Zhang X;Liu X;Zhou W;Du Q;Yang M;Ding Y;Hu R
结肠部的慢性炎症与结直肠癌(CRC)的风险增加有关。促炎细胞因子是在肿瘤微环境中产生的，与不良的临床结果相关。据报道，肿瘤浸润性T细胞在结肠癌的发生发展中起重要作用。在这项研究中，我们证明了吲哚胺2，3-双加氧酶(IDO)催化的代谢产物犬尿氨酸(Kyn)是IDO介导的T细胞功能所必需的，而获得性免疫确实在CRC中发挥了关键作用。用结肠癌细胞上清液培养活化的T细胞和小鼠脾淋巴细胞，体外测定IDO1-Kyn-芳香烃(AhR)受体轴。在体内建立偶氮甲烷(AOM)/葡聚糖硫酸钠(DSS)诱导的IDO-/-、Rag1-/-和野生型小鼠结直肠癌模型，检测各组肿瘤相关T淋巴细胞浸润和Kyn/AhR信号通路的变化。Kyn促进AhR核转位通过改善AhR与Foxp3启动子之间的相互作用，增加调节性T细胞(Tregs)标志物Foxp3的转录。此外，与WT小鼠相比，AOM/DSS治疗的IDO-/-小鼠在结肠中的肿瘤负担更少、更小，Treg更少，CD8+T细胞更多，而Kyn管理取消了这一调节。与野生型小鼠相比，RAG1-/-小鼠对AOM/DSS诱导的结肠炎相关性结肠癌(CRC)更敏感，提示T细胞介导的获得性免疫在CRC中确实起着关键作用。我们证明，抑制IDO可以减少Kyn/AhR介导的Treg分化，并可能成为预防和治疗炎症相关结肠癌的有效策略。
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. 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. 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. 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.
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影响因子：
10.1
作者：
通讯作者：
--
影响因子：
8.8
作者：
Ino, K;Yoshida, N;Kajiyama, H;Shibata, K;Yamamoto, E;Kidokoro, K;Takahashi, N;Terauchi, M;Nawa, A;Nomura, S;Nagasaka, T;Takikawa, O;Kikkawa, F
通讯作者：
Kikkawa, F
影响因子：
4.4
作者：
Burchill, Matthew A.;Yang, Jianying;Farrar, Michael A.
通讯作者：
Farrar, Michael A.
影响因子：
6.4
作者：
Liu, Xiuting;Zhou, Wei;Hu, Rong
通讯作者：
Hu, Rong
影响因子：
11.5
作者：
Brandacher, G;Perathoner, A;Amberger, A
通讯作者：
Amberger, A