Upregulation of programmed cell death ligand 1 promotes resistance response in non‐small‐cell lung cancer patients treated with neo‐adjuvant chemotherapy

• Published in: Cancer science 2016-11, Vol.107 (11), p.1563-1571
• Main Authors: Zhang, Panpan, Ma, Yuanyuan, Lv, Chao, Huang, Miao, Li, Mingzhen, Dong, Bin, Liu, Xijuan, An, Guo, Zhang, Wenlong, Zhang, Jianzhi, Zhang, Liyi, Zhang, Shanyuan, Yang, Yue
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Apoptosis; B7-H1 Antigen - deficiency; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell culture; Cell death; Cell Line, Tumor; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic - drug effects; Humans; Kinases; Ligands; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphocytes; Lymphocytes, Tumor-Infiltrating - metabolism; Medical prognosis; Melanoma; Mice; Multiple myeloma; Neoadjuvant Therapy; non‐small‐cell lung cancer; Original; Patients; PD-L1 protein; PD‐L1; Phosphatidylinositol 3-Kinases - metabolism; Prognosis; Proteins; Proto-Oncogene Proteins c-akt - metabolism; R&D; Research & development; Ribonucleic acid; RNA; Signal Transduction - drug effects; Studies; Surgery; Tumor cell lines; tumor infiltrating lymphocyte; Tumors; Up-regulation; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13072

To assess the association of the programmed cell death ligand 1 (PD‐L1) with cisplatin‐based neo‐adjuvant chemotherapy (NAC) response, we investigated the level of PD‐L1 and found increased PD‐L1 expression in chemo‐resistant tumors compared with chemo‐sensitive tumors according to RNA‐Seq analysis. In a cohort of 92 patients with NAC, the positive staining of PD‐L1 was correlated with TNM stage, lower sensitive‐response rates and shorter overall survival rates. In another 30 paired tumor specimens pre‐ and post‐chemotherapy, the patients with high PD‐L1 expression post‐chemotherapy had a worse outcome and higher stable disease rate. CD8+ tumor‐infiltrating lymphocytes were found to be related to chemosensitive response and better prognosis and negative PD‐L1 expression. Furthermore, in two patient‐derived xenograft models and cell lines A549 and PC‐9, cisplatin upregulated PD‐L1 expression, and the enhancement of PD‐L1 in cancer cell lines was in a drug dose‐dependent manner. Moreover, the depletion of PD‐L1 significantly reduced cisplatin resistance. When phosphatidylinositol 3‐kinase/protein kinase B signaling was inhibited by corresponding inhibitors, PD‐L1 expression was downregulated and apoptosis was upregulated in the cisplatin‐treated cancer cells. These results suggest that the upregulation of PD‐L1 promotes a resistance response in lung cancer cells that might be through activation of the phosphatidylinositol 3‐kinase/protein kinase B pathway and suppression of tumor‐infiltrating lymphocytes. The high expression of PD‐L1 after NAC could be an indication of therapeutic resistance and poor prognosis in patients with non‐small‐cell lung cancer. We explored PD‐L1 was induced in NSCLC patients with chemo‐resistance. PD‐L1 expression was associated with the poor prognosis for NSCLC patients. PD‐L1 expression changed before and after NAC for NSCLC tissues.