Upregulation of programmed death ligand-1 by radiation through the pathways downstream of epidermal growth factor receptor in glioma

Abstract

Objective To investigate the role of epidermal growth factor receptor (EGFR) signaling pathway in the upregulation of programmed death ligand-1 (PD-L1) caused by radiation (RT) and explore new strategies for the treatment of glioma. Methods Tissue microarrays (TMA) which contained glioma cancer specimens from 64 patients was used to examine the correlation between PD-L1 and EGFR levels. Furthermore, we performed experiments in vitro to investigate the role of EGFR pathway in RT-induced PD-L1 expression using human glioma cell lines U87 and U251. Results High PD-L1 expression was identified in 28 (43.8%) of 64 glioma specimens, and high EGFR expression was evident in 31 (48.4%) of 64 glioma specimens. There was a significant correlation between PD-L1 and EGFR protein levels in glioma specimens (χ2=5.000, P=0.025). High PD-L1 expression was significantly associated with patients’ age (χ2=11.460, P=0.001) and grade (χ2=7.110, P=0.008). The protein and mRNA levels of PD-L1 were both significantly upregulated by RT (t=10.292, P=0.000; t=52.171, P=0.000). Only the phosphorylated EGFR and janus protein tyrosine kinase (JAK) 2 were induced by RT (t=10.485, P=0.001; t=8.911, P=0.001). Besides, inhibition of EGFR pathway could abrogate the upregulation of PD-L1 caused by RT (t=0.758, P=0.490). The combination of RT with EGFR inhibitor had the same effect on enhancing antitumor immune response compared with the combination of RT with PD-L1 neutralizing antibody (Ab). However, RT combined with PD-L1 Ab plus AG490 did not further enhance the effect. Conclusion RT could upregulate the PD-L1 expression through the pathways downstream of EGFR in glioma. RT combined with EGFR inhibitor may become a new strategy for glioma. Key words: Programmed death ligand-1; Epidermal growth factor receptor; Radiotherapy; Combination therapy; Glioma