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

19 Scopus citations

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

ASJC Scopus subject areas

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

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    Wang, G. Z., Zhang, L., Zhao, X. C., Gao, S. H., Qu, L. W., Yu, H., Fang, W. F., Zhou, Y. C., Liang, F., Zhang, C., Huang, Y. C., Liu, Z., Fu, Y. X., & Zhou, G. B. (2019). The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy. Nature communications, 10(1), [1125]. https://doi.org/10.1038/s41467-019-08887-7