Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells

被引:152
作者
Liu, Yuying [1 ,2 ,3 ]
Liang, Xiaoyu [1 ,2 ]
Yin, Xiaonan [1 ,2 ]
Lv, Jiadi [1 ,2 ]
Tang, Ke [4 ]
Ma, Jingwei [4 ]
Ji, Tiantian [4 ]
Zhang, Huafeng [1 ,2 ]
Dong, Wenqian [1 ,2 ]
Jin, Xun [1 ,2 ]
Chen, Degao [1 ,2 ]
Li, Yanchun [1 ,2 ]
Zhang, Songyan [5 ]
Xie, Heidi Q. [5 ]
Zhao, Bin [5 ]
Zhao, Tong [6 ]
Lu, Jinzhi [1 ,2 ]
Hu, Zhuo-Wei [7 ,8 ]
Cao, Xuetao [1 ,2 ]
Qin, F. Xiao-Feng [8 ,9 ,10 ]
Huang, Bo [1 ,2 ,3 ,4 ]
机构
[1] Chinese Acad Med Sci, Inst Basic Med Sci, Natl Key Lab Med Mol Biol, Beijing 100005, Peoples R China
[2] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Immunol, Beijing 100005, Peoples R China
[3] Chinese Acad Med Sci, Clin Immunol Ctr, Beijing 100005, Peoples R China
[4] Huazhong Univ Sci & Technol, Dept Biochem & Mol Biol, Tongji Med Coll, Wuhan 430030, Peoples R China
[5] Chinese Acad Sci, Res Ctr Ecoenvironm Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China
[6] Chinese Acad Sci, Inst Microbiol, Beijing 100101, Peoples R China
[7] Chinese Acad Med Sci, Mol Immunol & Pharmacol Grp, State Key Lab Bioact Subst & Funct Nat Med, Inst Mat Med, Beijing 100050, Peoples R China
[8] Peking Union Med Coll, Beijing 100050, Peoples R China
[9] Chinese Acad Med Sci, Ctr Syst Med, Inst Basic Med Sci, Beijing 100005, Peoples R China
[10] Suzhou Inst Syst Med, Suzhou 215123, Peoples R China
来源
NATURE COMMUNICATIONS | 2017年 / 8卷
基金
中国国家自然科学基金;
关键词
ARYL-HYDROCARBON RECEPTOR; INDOLEAMINE 2,3-DIOXYGENASE; T-CELLS; PD-1; BLOCKADE; CANCER; EXPRESSION; RESISTANCE; APOPTOSIS; MELANOMA; MICROPARTICLES;
D O I
10.1038/ncomms15207
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Interactions with the immune system may lead tumorigenic cells into dormancy. However, the underlying molecular mechanism is poorly understood. Using a 3D fibrin gel model, we show that IFN-gamma induces tumour-repopulating cells (TRCs) to enter dormancy through an indolamine 2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn)-aryl hydrocarbon receptor (AhR)-p27 dependent pathway. Mechanistically, IFN-gamma signalling triggers differentiated tumour cell apoptosis via STAT1; however, when IDO1 and AhR are highly expressed as in TRCs, IFN-gamma results in IDO1/AhR-dependent p27 induction that prevents STAT1 signalling, thus suppressing the process of cell death and activating the dormancy program. Blocking the IDO/AhR metabolic circuitry not only abrogates IFN-gamma-induced dormancy but also results in enhanced repression of tumour growth by IFN-gamma-induced apoptosis of TRCs both in vitro and in vivo. These data present a previously unrecognized mechanism of inducing TRC dormancy by IFN-gamma, suggesting a potential effective cancer immunotherapeutic modality through the combination of IFN-gamma and IDO/AhR inhibitors.
引用
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页数:15
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