PD-L1 Promotes Tumor Progression, Chemotherapy Resistance, and Poor Clinical Out
PUBLISHED: 2015-11-26  580 total views, 2 today

Zhang Panpan1, Yuanyuan Ma2

1Peking University CancerHospital & Institute, Beijing , China, 2Peking university cancer hospital

 

Objective:Although neoadjuvant chemotherapy (NAC)for advanced lung cancer can improve operability and local disease control, theduration of benefit is limited before resistance develops. PD-L1, which was aco-stimulatory molecule, interacting with PD-1, has a crucial role in T-cellregulation in immune response. Studys remain incombining chemotherapy andimmune therapies to overcome resistance. Method: In the study, we usedRNA-Seq to evaluategene profiling in non-small lung cancer tissues. Weperformed immunohistochemistry, quantitative real-time PCR (qRT-PCR) and flowcytometry (FACS) techniques toinvestigate PD-L1 expression in clinicalsamplesand lung cancer cell lines. The statistical method of k-m was used to analyze thecorrelation between PD-L1 expression level and disease free survival (DFS) oflung cancer patients. Result: Firstly, weidentified PD-L1 wasup-regulated in the stable disease (SD) lung cancer patients by the RNA-Seqanalysis. Therefore, we performed IHC evaluation in the 96 patients of NSCLCwho received NAC. In patients who had SD to NAC, there was a rise in theexpression of PD-L1 compared with patients with PR (P=0.023), andpatients with NAC (n=96) had significantly high rate of positive PD-L1expression compared with those without NAC (n=116, P=0.0001). Meanwhile, patientswith PD-L1 (−) had much better DFS compared to those who were PD-L1 (+). Thechemotherapy of lung cancer can induce the expression of PD-L1, which may beone of the resistance mechanisms of NAC. Changes in PD-L1 expression were examinedin vitro and vivo. Inhibition of the PI3K/AKT pathway reduced the up-regulationof PD-L1 induced by cisplatin, suggesting an involvement of PI3K/AKT pathway inup-regulation of PD-L1. Moreover, knockdown of PD-L1 canlead to an increase inapoptosis, as well as cisplatin-induced apoptosis. Andcaspase 7 might play animportant role in the apoptosis of lung cancer cells after the knockdown ofPD-L1. Conclusion: These findings support provide a relationship betweenPD-L1 expression and chemoresistance. All in all, these results suggest the useof PD-L1 inhibitor with chemotherapy after surgery, in lung cancer patients whoreceived SD status after NAC.

 

Key Words: PD L1  chemoresistance  neoadjuvant therapy


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