The Biological Function And Applied Research Of EGFR/PD-L1 Pathway Activated By Radiotherapy In Glioma

Objectives: 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 were 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(X2=5.00,P=0.025).High PD-L1 expression was significantly associated with patients' age(X2=11.46,P=0.001)and grade(X2=7.11,P=0.008).At 48 h after 5Gy irradiation,the protein and m RNA levels of PD-L1 were both significantly upregulated by RT in U87 cells(t=10.292,P=0.000;t=52.171,P=0.000);the phosphorylated EGFR was also induced by RT(t=10.485,P=0.001).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 has 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.Conclusions: 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.