Decitibine improve the efficiency of anti-PD-1 therapy via activating the response to IFN/PD-L1 signal of lung cancer cells

作者：Lai, Qi; Wang, Haiyong; Li, Angui; Xu, Yinhui; Tang, Liang; Chen, Qiang; Zhang, Chunfang; Gao, Yang; Song, Jianfei^*; Du, Zhenzong^*

来源：Oncogene, 2018, 37(17): 2302-2312.

DOI：10.1038/s41388-018-0125-3

• PD-L1 EXPRESSION
• GENE-EXPRESSION
• IFN-GAMMA
• IMMUNOTHERAPY
• PATHWAY

IFN-gamma-induced PD-L1 expression represents the existence of tumor-specific T cells, which predicts high-response rate to anti-PD-1/L1 therapy, but loss-of-function of IFN signals (e.g., JAK mutation) induces adaptive immune resistance in patients with low-response rate. Interferon regulatory factors (IRF) are frequently epigenetic silenced in carcinogenesis, while the role of methylation in anti-PD-1/L1 therapy remains unclear. We here investigated the methylation status of IFN-gamma related genes IRF1/8 and IFN-alpha/beta-related genes IRF3/7 in lung cancer tissues and found that only highly methylated IRF1 and 7 negatively correlated to cd274 (coding PD-L1) expression, similar to JAK mutation. Interestingly, decitibine (DAC) as methylation inhibitor could hypomethylate IRF1/7 to restore PD-L1 level. Meanwhile, IRF7 enhanced constitutive PD-L1 expression, which was independent of IFN-gamma though directly promote transcription of PD-L1, leading to abrogating cytotoxic T lymphocytes (CTLs) generation which could be restored by anti-PD-L1 antibody, or siRNA-IRF7. The supplement of DAC to anti-PD-1 therapy in vivo improve the efficiency of anti-tumor with less methylated IRF1/7, more interferon-related genes expression (e.g., CXCL9) and IFN-gamma/CD8+ T-cells infiltrations, suggesting that additional treatment of DAC could rescue the ability to response to IFN in lung cancer patients with anti-PD-1/L1 therapy resistance.

• 出版日期2018-4
• 单位中南大学; 西南医科大学; 广西壮族自治区人民医院; 桂林医学院