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

Gui-Zhen Wang, Li Zhang, Xin-Chun Zhao, San-Hui Gao, Li-Wei Qu, Hong Yu, Wen-Feng Fang, Yong-Chun Zhou, Fan Liang, Chen Zhang, Yun-Chao Huang, Zhihua Liu, Yang-Xin Fu and Guang-Biao Zhou ()
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Gui-Zhen Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Li Zhang: Sun Yat-Sen University Cancer Center
Xin-Chun Zhao: Chinese Academy of Medical Sciences and Peking Union Medical College
San-Hui Gao: Chinese Academy of Medical Sciences and Peking Union Medical College
Li-Wei Qu: Chinese Academy of Sciences & University of Chinese Academy of Sciences
Hong Yu: Chinese Academy of Medical Sciences and Peking Union Medical College
Wen-Feng Fang: Sun Yat-Sen University Cancer Center
Yong-Chun Zhou: the Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital)
Fan Liang: Chinese Academy of Sciences & University of Chinese Academy of Sciences
Chen Zhang: Chinese Academy of Sciences & University of Chinese Academy of Sciences
Yun-Chao Huang: the Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital)
Zhihua Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Yang-Xin Fu: University of Texas Southwestern Medical Center
Guang-Biao Zhou: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08887-7

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