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BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer

Oncogene volume 36, pages 6235–6243 (2017)Cite this article

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Abstract

Non-small cell lung cancer (NSCLC) is one of the most common and malignant carcinoma worldwide, and the incidence and mortality are increasing rapidly. Immunotherapy targeting programmed death 1/programmed death ligand 1 (PD-L1) signaling has shown prominent clinical effects in treating NSCLC; however, a poor understanding of the associated regulating molecular mechanisms of PD-L1 has become one of the biggest obstacles for further improving efficacy. Bridging integrator-1 (BIN1) can regulate numerous cancer-related molecules to exert multiple tumor-suppressing effects by either interacting or not interacting with c-MYC. In the present study, we observed that there exists a negative correlation between the expression of PD-L1 and BIN1 in NSCLC tissues. The expression levels of BIN1 and PD-L1 were significantly related to the tumor, lymph node and metastasis grade (TNM) stage, invasion range and lymph node metastasis. Simultaneously, for NSCLC patients, the expression statuses of BIN1 and PD-L1 might be independent prognostic factors. Furthermore, the expression of tumor-infiltrating lymphocytes was positively associated with BIN1 expression and negatively related to PD-L1 expression in NSCLC tissues. Importantly, we showed that PD-L1 was under the control of BIN1. In addition, the overexpression of BIN1 could inhibit the c-MYC and epithelial growth factor receptor (EGFR)-dependent PD-L1 expression and reverse the suppressive immuno-microenvironment in vivo. Taken together, our findings indicated that BIN1 restoration in NSCLC could reverse PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/mitogen-activated protein kinase pathways.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81201607), Postdoctoral Fund of China (2013M540883), and Outstanding Youth Foundation of Hebei Province (H2014206320).

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  1. J Wang and Y Jia: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, China

    J Wang, Y Jia, X Zhang, X Wang, X Han, Y Wang & L Liu

  2. Department of Pathology, Hebei Medical University, Shijiazhuang, China

    S Zhao

  3. Research Center, Fourth Hospital of Hebei Medical University and Hebei Cancer Institute, Shijiazhuang, China

    M Ma

  4. State Key Laboratory of Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    J Shi

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Wang, J., Jia, Y., Zhao, S. et al. BIN1 reverses PD-L1-mediated immune escape by inactivating the c-MYC and EGFR/MAPK signaling pathways in non-small cell lung cancer. Oncogene 36, 6235–6243 (2017). https://doi.org/10.1038/onc.2017.217

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