ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2022; 18(11):4275-4288. doi:10.7150/ijbs.73275 This issue Cite
Research Paper
CCL20 promotes lung adenocarcinoma progression by driving epithelial-mesenchymal transition
1. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
2. Department of Oncology, Renmin Hospital of Wuhan University, 238th Jiefang Road, Wuhan 430060, China.
3. Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
4. Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
#These authors contributed equally to this work.
Abstract
C-C motif chemokine ligand 20 (CCL20) participates in multiple oncogenic processes, but its role in lung adenocarcinoma (LUAD) is unclear. Herein, we explored the mechanism by which CCL20 works in LUAD progression. We performed bioinformatical analyses based on the complete transcriptome sequencing data from 1544 LUAD cases in 4 independent cohorts to evaluate signaling pathways regulated by CCL20. We established A549 and H358 cell lines with CCL20 knockdown to explore how CCL20 promotes tumor progression in vitro and in vivo experiments. Using another independent cohort of 348 urothelial carcinoma patients treated with the anti-PD-L1 agent (atezolizumab), we explored the synergistic effect of CCL20 and TGF-β on immunotherapy efficacy. High CCL20 expression is a poor prognostic marker for LUAD patients, and is associated with enhanced epithelial-mesenchymal transition (EMT), inflammatory response, and activated TNF pathway in LUAD. CCL20 knockdown restrained the EMT process and cell proliferation of LUAD cells in vitro and in vivo. Low CCL20 expression blocked the detrimental effects of high TGF-β on survival and effectively improved patients' response to anti-PD-L1 therapy. Collectively, we revealed the underlying mechanisms by which CCL20 promotes LUAD progression based on the largest sample size. The synergistic inhibitory effect of CCL20 and TGF-β on immune-checkpoint blockade therapy efficacy provides new views of immunotherapy resistance.
Keywords: CCL20, EMT, immune checkpoint blockade, tumor immunology
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