Chemotherapy induces PD-L1 in esophageal squamous cell carcinoma

Abstract

Introduction Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive and lethal cancers. Chemoresistance is a major obstacle in effective treatment to ESCC patients. Programmed death ligand-1 (PD-L1) is an immunoregulatory protein that is overexpressed in various cancers. The interaction between PD-L1 and programmed death-1 (PD-1) plays an important role in evasion from host immunosurveillance of cancer cells. PD-L1 up-regulation contributes to chemoresistance in several cancers, but little is known with respect to changes associated with chemotherapy treatment in ESCC. Material and method Tissue microarray consisting 84 ESCC tumors from Chinese patients was used to determine the PD-L1 expression rate and its correlation with clinicopathological parameters. Immunohistochemical (IHC) staining was performed with PD-L1 antibody and the staining intensity was scored. Two ESCC cell lines, KYSE150 and SLMT, were used. Cells were treated with either 5-Flurouracil plus cisplatin or carboplatin plus paclitaxel, which are the common regimens used for ESCC patients. The regulation of PD-L1 expression by the EGFR pathway and ERK pathway was studied using Erlotinib (EGFR inhibitor) and AZD6244 (MEK inhibitor). For the in vivo studies, esophageal orthotopic mouse model was used. KYSE150 cell were injected into the mouse esophagus. Mice were administered with 5-Flurouracil plus cisplatin or carboplatin plus paclitaxel by intraperitoneal injection. The change in PD-L1 expression is then evaluated by Western blotting and IHC staining. Results and discussion The expression rate of PD-L1 in Chinse ESCC patients was 21% (18/84) and the patients with positive PD-L1 staining were associated with later stage (stage III and IV) of the disease. Also, high PD-L1 expression was associated with lymph node metastasis. Both in vitro and in vivo studies demonstrate that the level of PD-L1 expression increased after the treatment with 5-Flurouracil plus cisplatin or carboplatin plus paclitaxel. In vitro study shows that the elevated PD-L1 level sustained even after the drugs were moved. By using pathway inhibitors, we demonstrate the increase in PD-L1 expression in response to chemotherapy was regulate by the EGFR pathway and its downstream ERK pathway, as the PD-L1 level attenuated when Erlotinib or AZD6244 was added. Conclusion PD-L1 expression was increased following treatment with chemotherapy in ESCC cell lines, suggesting that combining chemotherapy with PD-L1 blockade may improve treatment in ESCC patients.