The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy
Open accessAbstract
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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Smoking exposure potently activates the cellular aryl hydrocarbon receptor, as cigarette smoke contains exogenous ligands for AhR such as TCDD and polycyclic aromatic hydrocarbons like benzo(a)pyrene.
“Smoking exposure potently activates the cellular Aryl hydrocarbon receptor (AhR) [108], as cigarette smoke contains a large number of exogenous ligands for AhR, such as dioxin-like derivatives represented by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and a variety of polycyclic aromatic hydrocarbon (PAH)-based compounds such as benzo(a)pyrene (BaP) [109].”
From An Overlooked Bone Metabolic Disorder: Cigarette Smoking-Induced Osteoporosis (2022) · cites this paper as [108]
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References 55 · Cited by 213
- Authors
- 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.
- Affiliations
- Chinese Academy of Sciences (CN)
- Sun Yat-sen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Beijing University of Chinese Medicine (CN)
- Kunming Medical University (CN)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Zhou, Guang-Biao
- Venue
- Nature Communications
- Published
- 2019-03-08
- Volume
- 10
- Issue
- 1
- Pages
- 1125-1125
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6408580
- OpenAlex
- W2921867919
- Cited by
- 213
- References
- 55
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 35 · 2023: 33 · 2022: 32 · 2021: 40 · 2020: 29 · 2019: 10
- FWCI
- 11.60
- Type
- journal article
- Language
- en
- Update notices
- correction (2022-06-22)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Bristol-Myers Squibb
- National Natural Science Foundation of China (81672765, 81425025, 81830093, 81802796, 2016YFC0905500)
- National Key Research and Development Program of China (2016YFC0905500, 81672765, 81425025)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- aryl hydrocarbon receptor, PD-L1 expression, tobacco smoke, benzo[a]pyrene, lung cancer, immune evasion, anti-PD-1 therapy, pembrolizumab, immunotherapy response prediction, lung epithelial cells, carcinogenesis
- MeSH terms
- Animals, Antibodies, Monoclonal, Benzo(a)pyrene, Benzoflavones, Carcinogens, Disease Models, Animal, Female, Humans, Immunotherapy, Lung, Lung Neoplasms, Mice, Inbred C57BL, Smoking, Nicotiana, Signal Transduction, Gene Expression Regulation, Neoplastic, Survival Analysis, Receptors, Aryl Hydrocarbon, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Small Cell Lung Carcinoma, B7-H1 Antigen
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