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Oncogene. 2018 Apr;37(17):2302-2312. doi: 10.1038/s41388-018-0125-3. Epub 2018 Feb 9.

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

Author information

1
Department of Thoracic Surgery, Xiangya Hospital Cental South University, Changsha, Hunan, China.
2
Department of Thoracic Surgery, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China.
3
Department of Thoracic and Cardiovascular Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, China.
4
Department of Cardiothoracic Surgery, Affiliated Nanxi Shan Hospital of Guilin Medical University; Nanxi Shan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China.
5
Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, China.
6
Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, China. guilinsjf@163.com.
7
Department of Thoracic Surgery, Xiangya Hospital Cental South University, Changsha, Hunan, China. duzhenzong@sina.com.
8
Department of Cardiothoracic Surgery, Affiliated Nanxi Shan Hospital of Guilin Medical University; Nanxi Shan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China. duzhenzong@sina.com.

Abstract

IFN-γ-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-γ related genes IRF1/8 and IFN-α/β-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-γ 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-γ/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.

PMID:
29422611
DOI:
10.1038/s41388-018-0125-3

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