Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation

被引：406

作者：

Liu, Yuying ^{[1
,2
,3
,4
]}

Liang, Xiaoyu ^{[1
,2
,3
]}

Dong, Wenqian ^{[1
,2
,3
]}

Fang, Yi ^{[5
]}

Lv, Jiadi ^{[1
,2
,3
]}

Zhang, Tianzhen ^{[1
,2
,3
]}

Fiskesund, Roland ^{[1
,2
,3
]}

Xie, Jing ^{[1
,2
,3
]}

Liu, Jinyan ^{[1
,2
,3
]}

Yin, Xiaonan ^{[1
,2
,3
]}

Jin, Xun ^{[1
,2
,3
]}

Chen, Degao ^{[1
,2
,3
]}

Tang, Ke ^{[6
]}

Ma, Jingwei ^{[6
]}

Zhang, Huafeng ^{[6
]}

Yu, Jing ^{[7
]}

Yan, Jun ^{[7
]}

Liang, Huaping ^{[7
]}

Mo, Siqi ^{[1
,2
,3
]}

Cheng, Feiran ^{[1
,2
,3
]}

Zhou, Yabo ^{[1
,2
,3
]}

Zhang, Haizeng ^{[5
]}

Wang, Jing ^{[5
]}

Li, Jingnan ^{[8
]}

Chen, Yang ^{[8
]}

Cui, Bing ^{[9
]}

Hu, Zhuo-Wei ^{[9
]}

Cao, Xuetao ^{[1
,2
,3
]}

Qin, F. Xiao-Feng ^{[10
,11
]}

Huang, Bo ^{[1
,2
,3
,4
,6
]}

机构：

[1] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Immunol, Beijing, Peoples R China

[2] Chinese Acad Med Sci, Natl Key Lab Med Mol Biol, Inst Basic Med Sci, Beijing, Peoples R China

[3] Peking Union Med Coll, Beijing, Peoples R China

[4] CAMS, Clin Immunol Ctr, Beijing 100005, Peoples R China

[5] CAMS, Natl Canc Ctr, Canc Hosp, Beijing 100005, Peoples R China

[6] Huazhong Univ Sci & Technol, Tongji Med Coll, Dept Biochem & Mol Biol, Wuhan 430030, Hubei, Peoples R China

[7] Third Mil Med Univ, Inst Surg Res, State Key Lab Trauma Burns & Combined Injury, Daping Hosp,Dept 1, Chongqing 400042, Peoples R China

[8] CAMS, Peking Union Med Coll Hosp, Dept Gastroenterol, Beijing 100005, Peoples R China

[9] CAMS, Inst Mat Med, Mol Immunol & Pharmacol Grp, State Key Lab Bioact Substance & Funct Nat Med, Beijing 100005, Peoples R China

[10] CAMS, Inst Basic Med Sci, Ctr Syst Med, Suzhou 215123, Peoples R China

[11] Suzhou Inst Syst Med, Suzhou 215123, Peoples R China

来源：

CANCER CELL | 2018年 / 33卷 / 03期

基金：

中国国家自然科学基金;

关键词：

ARYL-HYDROCARBON RECEPTOR; TRYPTOPHAN CATABOLISM; IFN-GAMMA; INDOLEAMINE 2,3-DIOXYGENASE; INTERFERON-GAMMA; DENDRITIC CELLS; MELANOMA; MICROENVIRONMENT; REJECTION; CANCER;

D O I：

10.1016/j.ccell.2018.02.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8(+) T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-g produced by CD8(+) T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8(+) T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.

引用

页码：480 / +

页数：22

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