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

• Published in: Nature communications Vol. 10; no. 1; pp. 1125 - 13
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.03.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 13/89; 13/95; 38/88; 42/89; 631/67/1612/1350; 692/4028/67/1612/1350; 82/1; 96/44; Adaptive immunity; Animal models; Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Anticancer properties; Antitumor activity; Aromatic compounds; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Benzo(a)pyrene; Benzo(a)pyrene - toxicity; Benzoflavones - pharmacology; Cancer; Carcinogenesis; Carcinogens; Carcinogens - toxicity; Cell Line, Tumor; Cigarette smoke; Disease Models, Animal; Epithelial cells; Epithelium; Female; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Humans; Hydrocarbons; Immunity; Immunotherapy; Immunotherapy - methods; Lung - drug effects; Lung - immunology; Lung - pathology; Lung cancer; Lung Neoplasms - etiology; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - therapy; Mice; Mice, Inbred C57BL; Monoclonal antibodies; multidisciplinary; Patients; PD-1 protein; PD-L1 protein; Pembrolizumab; Pyrene; Receptors; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - immunology; Science; Signal Transduction; Small Cell Lung Carcinoma - etiology; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - mortality; Small Cell Lung Carcinoma - therapy; Smoke; Smoking; Smoking - adverse effects; Survival Analysis; Synergism; Targeted cancer therapy; Therapeutic applications; Therapeutic targets; Tobacco; Tobacco smoke; Tumorigenesis; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08887-7

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. Lung cancer patients who smoke show a better response to immunotherapy than non-smokers. Here, the authors show that tobacco smoke induces PD-L1 expression on lung epithelial cells via AhR that is associated with benefits of PD-1 inhibitor in patients, shedding new lights on lung carcinogenesis and immunotherapy.