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

Oncogene volume 37, pages 2302–2312 (2018)Cite this article

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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.

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Acknowledgements

This work was supported by the Natural Science Foundation of Guangxi (2016GXNSFAA380138) and Science Research and Technology Development Plan of Guangxi (2015BC12007).

Author contributions

Q.L., H.W., A.L., J.S., and Z.D. designed the experiments. Development of methodology: Q.L., H.W., A.L., Y.X., L.T., Q.C., C.Z., and Y.G. Q.L., H.W., J.S., and Z.D. analyzed the data and wrote the manuscript with all approving the final version.

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Authors and Affiliations

  1. Department of Thoracic Surgery, Xiangya Hospital Cental South University, Changsha, Hunan, China

    Qi Lai, Chunfang Zhang, Yang Gao & Zhenzong Du

  2. Department of Thoracic Surgery, Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China

    Qi Lai

  3. Department of Thoracic and Cardiovascular Surgery, The Affiliated Hospital of Guilin Medical University, Guilin, China

    Haiyong Wang & Angui Li

  4. Department of Cardiothoracic Surgery, Affiliated Nanxi Shan Hospital of Guilin Medical University; Nanxi Shan Hospital of Guangxi Zhuang Autonomous Region, Guilin, Guangxi, China

    Yinhui Xu, Liang Tang & Zhenzong Du

  5. Department of Thoracic and Cardiovascular Surgery, The Second Affiliated Hospital of Guilin Medical University, Guilin, China

    Qiang Chen & Jianfei Song

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  1. Qi Lai
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Correspondence to Jianfei Song or Zhenzong Du.

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Lai, Q., Wang, H., Li, A. et al. Decitibine improve the efficiency of anti-PD-1 therapy via activating the response to IFN/PD-L1 signal of lung cancer cells. Oncogene 37, 2302–2312 (2018). https://doi.org/10.1038/s41388-018-0125-3

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