The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy

被引:156
作者
Wang, Gui-Zhen [1 ,2 ,3 ,4 ]
Zhang, Li [5 ,6 ,7 ]
Zhao, Xin-Chun [1 ,2 ,3 ,4 ]
Gao, San-Hui [1 ,2 ]
Qu, Li-Wei [3 ,4 ]
Yu, Hong [1 ,2 ,8 ]
Fang, Wen-Feng [5 ,6 ,7 ]
Zhou, Yong-Chun [9 ]
Liang, Fan [3 ,4 ]
Zhang, Chen [3 ,4 ]
Huang, Yun-Chao [9 ]
Liu, Zhihua [1 ,2 ]
Fu, Yang-Xin [10 ]
Zhou, Guang-Biao [1 ,2 ,3 ,4 ]
机构
[1] Chinese Acad Med Sci, Natl Clin Res Ctr Canc, State Key Lab Mol Oncol, Natl Canc Ctr,Canc Hosp, Beijing 100021, Peoples R China
[2] Peking Union Med Coll, Beijing 100021, Peoples R China
[3] Chinese Acad Sci, Inst Zool, State Key Lab Membrane Biol, Beijing 100101, Peoples R China
[4] Univ Chinese Acad Sci, Beijing 100101, Peoples R China
[5] Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China
[6] Sun Yat Sen Univ, Canc Ctr, Collaborat Innovat Ctr Canc Med, Guangzhou 510060, Guangdong, Peoples R China
[7] Sun Yat Sen Univ, Canc Ctr, Med Oncol Dept, Guangzhou 510060, Guangdong, Peoples R China
[8] Beijing Univ Chinese Med, Sch Chinese Mat Med, 11 Bei San Huan Dong Lu, Beijing 100029, Peoples R China
[9] Kunming Med Univ, Affiliated Hosp 3, Dept Thorac Surg, Yunnan Tumor Hosp, Kunming 650106, Yunnan, Peoples R China
[10] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA
基金
中国国家自然科学基金; 国家杰出青年科学基金;
关键词
CIGARETTE-SMOKE; GENOMIC VARIATIONS; B7-H1; EXPRESSION; OPEN-LABEL; LUNG; RESISTANCE; BLOCKADE; NIVOLUMAB; DOCETAXEL; MULTICENTER;
D O I
10.1038/s41467-019-08887-7
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
Whether tobacco carcinogens enable exposed cells immune escape resulting in carcinogenesis, and why patients who smoke respond better to immunotherapies than non-smokers, remains poorly understood. Here we report that cigarette smoke and the carcinogen benzo (a) pyrene (BaP) induce PD-L1 expression on lung epithelial cells in vitro and in vivo, which is mediated by aryl hydrocarbon receptor (AhR). Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. In 37 patients treated with anti-PD-1 antibody pembrolizumab, 13/16 (81.3%) patients who achieve partial response or stable disease express high levels of AhR, whereas 12/16 (75%) patients with progression disease exhibit low levels of AhR in tumor tissues. AhR inhibitors exert significant antitumor activity and synergize with anti-PD-L1 antibody in lung cancer mouse models. These results demonstrate that tobacco smoke enables lung epithelial cells to escape from adaptive immunity to promote tumorigenesis, and AhR predicts the response to immunotherapy and represents an attractive therapeutic target.
引用
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页数:13
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