101. Epigenetically silenced PD-L1 confers drug resistance to anti-PD1 therapy in gastric cardia adenocarcinoma
- Author
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Zhuoyin Wang, Ruixin Li, Zhihao Hu, Junfeng Sun, Hengxuan Ding, Tianyu Zhu, and Guojun Wang
- Subjects
0301 basic medicine ,Pharmacology ,Messenger RNA ,biology ,business.industry ,Immunology ,Bisulfite sequencing ,Cancer ,Drug resistance ,Methylation ,medicine.disease ,Gastric Cardia Adenocarcinoma ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Hypomethylating agent ,030220 oncology & carcinogenesis ,PD-L1 ,medicine ,biology.protein ,Cancer research ,Immunology and Allergy ,business - Abstract
Objectives The anti-PD-1/PD-L1 therapy has been demonstrated safe and effective for cancer patients. However, our previous data showed that it had no obvious effects on gastric cardia adenocarcinoma (GCA). Thus, we investigated how the expression level of the PD-L1 was affected by the anti-PD-1 therapy, because it has been demonstrated that the PD-L1 level affects the therapeutic efficient of the anti-PD-1 therapy. Materials and methods The mRNA and protein levels of PD-L1 in the GCA tissues and corresponding normal tissues were determined by qPCR and ELISA. Promoter methylation was analyzed by bisulfite sequencing. Finally the methylation of PD-L1 promoter was confirmed in the mice. Results The level of PD-L1 was up-regulated in the GCA tissues when compared to the adjacent non-tumor tissues. The anti-PD1 therapy could reduce the PD-L1 levels in patients with cancer recurrence. The promoter of PD-L1 was more hypermethylated in the secondary GCA after the anti-PD-1 therapy when compared with the adjacent non-tumor tissues or the primary GCA without the anti-PD-1 therapy. Furthermore, the promoter methylation of PD-L1 could be induced by the anti-PD-1 therapy in the mice model. Finally, the anti-PD-1 plus DNA hypomethylating agent azacytidine could significantly suppressed the tumor growth better than the anti-PD-1 therapy. Conclusions Here we demonstrated that the unresponsiveness of GCA to the anti-PD-1 therapy might result from the promoter methylation and down-regulation of PD-L1. The anti-PD-1 plus azacytidine might be a more promising approach to treat GCA.
- Published
- 2019