Open AccessUpregulation of programmed cell death ligand 1 promotes resistance response in non‐small‐cell lung cancer patients treated with neo‐adjuvant chemotherapy
Author(s) -
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
Publication year - 2016
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13072
Subject(s) - downregulation and upregulation , cisplatin , chemotherapy , cancer research , lung cancer , apoptosis , programmed cell death , medicine , cancer , kinase , protein kinase a , biology , pathology , microbiology and biotechnology , biochemistry , gene
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 ‐ L 1 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 ‐ L 1 expression post‐chemotherapy had a worse outcome and higher stable disease rate. CD 8 + tumor‐infiltrating lymphocytes were found to be related to chemosensitive response and better prognosis and negative PD ‐ L 1 expression. Furthermore, in two patient‐derived xenograft models and cell lines A 549 and PC ‐9, cisplatin upregulated PD ‐ L 1 expression, and the enhancement of PD ‐ L 1 in cancer cell lines was in a drug dose‐dependent manner. Moreover, the depletion of PD ‐ L 1 significantly reduced cisplatin resistance. When phosphatidylinositol 3‐kinase/protein kinase B signaling was inhibited by corresponding inhibitors, PD ‐ L 1 expression was downregulated and apoptosis was upregulated in the cisplatin‐treated cancer cells. These results suggest that the upregulation of PD ‐ L 1 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 ‐ L 1 after NAC could be an indication of therapeutic resistance and poor prognosis in patients with non‐small‐cell lung cancer.