Cigarette Smoke or Motor Vehicle Exhaust Exposure Induces PD-L1 Upregulation in Lung Epithelial Cells in COPD Model Rats

Abstract

A high smoking-independent chronic obstructive pulmonary disease (COPD) prevalence is observed in lung cancer patients. However, the underlying connection between these two diseases still remains unclear. Cigarette smoking and ambient air pollution are common risk factors for COPD and lung cancer. In this study, we established rat COPD model through exposure to cigarette smoke (CS) or motor vehicle exhaust (MVE). The model rats developed COPD-like phenotypes, manifested as lung functions decline, lung inflammation, emphysema-like alveolar enlargement and airway remodeling. The programmed death-ligand 1 (PD-L1), a factor contributing to immune escape of tumor cells, was overexpressed in lungs from COPD model rats, though more severe COPD phenotypes did not bring with further PD-L1 overexpression in lung. The upregulations of proinflammatory cytokines and PD-L1 were also observed in cultured human bronchial epithelial cells BEAS-2B upon treatment with cigarette smoke extract (CSE) or diesel-related particulate matter 2.5 (PM_2.5, SEM1650b). The inflammatory cytokines produced in BEAS-2B cells reflected the PD-L1 levels. Furthermore, ERK1/2, a kinase mediating PD-L1 upregulation in premalignant bronchial cells or NSCLC cells, and STAT1/3, which was reportedly associated with PD-L1 expression in lung tumors, were activated in COPD rats’ lungs or in BEAS-2B cells treated with CSE or PM_2.5. Therefore, we proposed that inflammation associated PD-L1 overexpression in airway epithelial cells could be the underlying factor facilitating lung cancer incidence in COPD.

Keywords:

• COPD
• lung cancer
• PD-L1
• CS
• MVE
• PM_2.5

Acknowledgments

We would like to thank Professor Wenju Lu for technical assistance in the establishment of MVE-induced COPD animal models.

Disclosure statement

The authors have no conflict of interest to declare.

Availability of data and material

This manuscript or the results included are original and have not been submitted for publication elsewhere.

Additional information

Funding

This study was supported by grants from the National Natural Science Foundation of China (81900033), Natural Science Foundation of Guangdong Province (2018A030313787, 2022A1515012504) and Basic and Applied Basic Research Project of Guangzhou Science and Technology Bureau (202102020129).

Notes on contributors

Huang Wenjie

Wenjie Huang conceived the idea for the project. Zhenhui Guo contributed to the design of the protocol. Rui Chen and Li Defu built the animal models, collected samples and drafted the manuscript. Lingling Wang and Yuanyuan Ye analyzed the data. Jiahui Dong and Richeng Xiong took part in the collection of samples. Wenjie Huang revised the manuscript critically. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.