Study Of Relation Between PD-L1 Expression And EGFR-TKIs Resistance Mechanism In Non-small Cell Lung Cancer

BackgroundSince EGFR gene mutation has been identified as a key driver gene variation,targeting EGFR signaling pathway has achieved a huge success in NSCLC.Despite superior clinical benefit,de novo resistance and acquired resistance is inevitable.Currently,some mechanisms of resistance to EGFR-TKIs have been revealed,including T790M mutation,MET amplification,or HER2 mutation and so on.However,these potential reseasons can not explain all the mechanism of resistance to EGFR-TKIs.Recently,it was reported that immune mechanisms were associated with driver gene mutation and involved in acquired resistance to MAPK inhibitors in melanoma.Given that immune mechanisms contributed resistance to target therapy existed and increased expression of PD-L1 was detected after acquired resistance to EGFR-TKIs,it's reasonable to assume that PD-L1 expression on tumor and immune cells may serve as a resistance source to target therapy in NSCLC with EGFR mutation.MethodsPatients diagnosed as advanced NSCLC treated with EGFR-TKIs at our hospital were collected,all of which synchronously received detection of EGFR status and PD-L1 expression.Progression free survival(PFS)was estimated from the firs time of oral administration to disease progression or death or last follow-up.All statistical analyses were performed using GraphPad Prism software(version 7.01)and IBM SPSS software(version 22.0;IBM Corp.,Armonk,NY).Kaplan-Meier curves and the log-rank test were used to analyses progression-free survival(PFS)according to PD-L1 expression.All reported P-values were two-tailed and differences were considered statistically significant at P<0.05.ResultsWe firstly uncovered the adverse impact of PD-L1 expression on the efficacy of EGFR-TKIs,especially in those with de novo resistance NSCLC,which inclined to reshape an inflamed immune phenotype of dual positive PD-L1 and CD8 and showed potential therapeutic sensitivity to PD-1 blockade.Furthermore,an increased of PD-L1 expression in tumor cells was found in a subset of patients after resitstance to EGFR-TKIs treatment.Meanwhile,the relation of PD-L1 expression and MET positive was identified both in our hospital data base and TCGA data base.According to the analysis of the expression profile of lung adenocarcinoma in the public database(TCGA),we found that the MET expression not only promoted the expression of PD-L1 in lung adenocarcinoma,but also activated the T-cell-IFN-gamma signaling pathway.On the evidence of previous research findings,we further dynamic monitored the biomarkers of T cell exhaustion in plasma during combined treatment of EGFR-TKIs and MET-TKIs in EGFR mutant patients with C-MET overexpression after acquired resistance to EGFR-TKIs.We similarly observed a rising trend of PD-L1 expression in peripheral blood lymphocyte during combined treatnment in NSCLC with MET positive,which comfired the involment of immune surveillance during target therapy in NSCLC.ConclusionsThe present work provide evidence that immune surveillance may confer resistance to tartgeted therapy in non-small cell lung cancer.We had discovered an adverse impact of PD-L1 expression on EGFR-TKIs efficacy and a dural positive of PD-L1/CD8 in patients with de novo resistance to EGFR-TKIs.Furthermore,we uncovered an obvious correlation between MET expression and PD-L1 expression and an activated T-effector and interferon-y associated gene pathway,which indicated the benefit from checkpoint inhibitors.Base on these findings,our study preliminary revealed that PD-L1 may served as a resistance source of target therapy in NSCLC patient treated with EGFR inhibitors.