Research Papers:

PD-L1 promoter methylation mediates the resistance response to anti-PD-1 therapy in NSCLC patients with EGFR-TKI resistance

Yan Zhang, Cheng Xiang _, Yuling Wang, Yuanyuan Duan, Ci Liu and Yajing Zhang

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Oncotarget. 2017; 8:101535-101544. https://doi.org/10.18632/oncotarget.21328

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Yan Zhang1, Cheng Xiang1, Yuling Wang2, Yuanyuan Duan1, Ci Liu1 and Yajing Zhang1

1Department of Oncology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050010, China

2Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050021, China

Correspondence to:

Cheng Xiang, email: [email protected]

Keywords: PD-L1 promoter methylation; non-small cell lung cancer; anti-PD-1 therapy; EGFR-TKI resistance

Received: July 28, 2017     Accepted: August 19, 2017     Published: September 27, 2017


The anti-PD-1/PD-L1 therapy has been demonstrated effective and safe for advanced NSCLC patients, especially for EGFR-TKIs (epidermal growth factor receptor - tyrosine kinase inhibitors) resistant NSCLC (non-small cell lung cancer) patients with EGFR mutations. However, whether the anti-PD-1/PD-L1 therapy also promotes drug resistance as EGFR-TKIs treatment remains unclear. Thus, we conducted the present study to investigate the effects of anti-PD-1 therapy on the expression of PD-L1, which is one important factor mediates the efficacy of anti-PD-1 therapy. To address the expression dynamics of PD-L1 after anti-PD-1 therapy, we first divided the patients into three groups according to the EGFR mutation status (wild type, L858R and T790M mutation). The PD-L1 was highly expressed in the NSCLC tissues than the corresponding normal tissues. After cancer recurrence, the PD-L1 was further up-regulated in patients treated with chemotherapy or EGFR-TKI therapy but decreased in the patients with anti-PD1 therapy. Promoter methylation analysis showed that the secondary NSCLC after cancer recurrence with anti-PD1 therapy had much higher promoter methylation level than the primary cancer tissue or normal tissues. In the mice model, the anti-PD-1 therapy could induce PD-L1 promoter methylation irrespective of EGFR mutation status. Combining DNA hypomethylating agent azacytidine with anti-PD-1 therapy could significantly further reduce the tumor size when comparing with the anti-PD-1 therapy alone. Our results demonstrated that the anti-PD-1 therapy might promote drug resistance through PD-L1 promoter methylation and down-regulation. And combining DNA hypomethylating agent azacytidine with anti-PD-1 therapy might be a promising approach to overcome the resistance.

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