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, Guang Biao Zhou

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number1125
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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tobacco
Aryl Hydrocarbon Receptors
Tobacco
Immunotherapy
hydrocarbons
lungs
smoke
antibodies
Smoke
carcinogens
Carcinogens
escape
Antibodies
Lung Neoplasms
Carcinogenesis
cancer
Epithelial Cells
Lung
Benzo(a)pyrene
immunity

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy. / Wang, Gui Zhen; Zhang, Li; Zhao, Xin Chun; Gao, San Hui; Qu, Li Wei; Yu, Hong; Fang, Wen Feng; Zhou, Yong Chun; Liang, Fan; Zhang, Chen; Huang, Yun Chao; Liu, Zhihua; Fu, Yang-Xin; Zhou, Guang Biao.

In: Nature communications, Vol. 10, No. 1, 1125, 01.12.2019.

Research output: Contribution to journalArticle

Wang, GZ, Zhang, L, Zhao, XC, Gao, SH, Qu, LW, Yu, H, Fang, WF, Zhou, YC, Liang, F, Zhang, C, Huang, YC, Liu, Z, Fu, Y-X & Zhou, GB 2019, 'The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy', Nature communications, vol. 10, no. 1, 1125. https://doi.org/10.1038/s41467-019-08887-7
Wang, Gui Zhen ; Zhang, Li ; Zhao, Xin Chun ; Gao, San Hui ; Qu, Li Wei ; Yu, Hong ; Fang, Wen Feng ; Zhou, Yong Chun ; Liang, Fan ; Zhang, Chen ; Huang, Yun Chao ; Liu, Zhihua ; Fu, Yang-Xin ; Zhou, Guang Biao. / The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.",
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