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

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.