title: Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy.
abstract: 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.
authors: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Panpan
authors: P
authors: Zhang
authors: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Yuanyuan
authors: Y
authors: Ma
authors: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Chao
authors: C
authors: Lv
authors: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Miao
authors: M
authors: Huang
authors: Beijing Center for Physical and Chemical Analysis, Beijing, China.
authors: Mingzhen
authors: M
authors: Li
authors: Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Bin
authors: B
authors: Dong
authors: Central Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Xijuan
authors: X
authors: Liu
authors: Department of Laboratory Animals, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Guo
authors: G
authors: An
authors: Department of Laboratory Animals, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Wenlong
authors: W
authors: Zhang
authors: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Jianzhi
authors: J
authors: Zhang
authors: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Liyi
authors: L
authors: Zhang
authors: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Shanyuan
authors: S
authors: Zhang
authors: Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.
authors: Yue
authors: Y
authors: Yang
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D051379:Mice; D020360:Neoadjuvant Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin
keywords: Chemoresistance; PD-L1; neoadjuvant therapy; non-small-cell lung cancer; tumor infiltrating lymphocyte