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

// Yan Zhang 1 , Cheng Xiang 1 , Yuling Wang 2 , Yuanyuan Duan 1 , Ci Liu 1 and Yajing Zhang 1 1 Department of Oncology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050010, China 2 Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050021, China Correspondence to: Cheng Xiang, email: chengxiangsjz@163.com 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 ABSTRACT 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.