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Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo

Author

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  • Huapan Fang

    (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
    University of Science and Technology of China
    Jilin Biomedical Polymers Engineering Laboratory
    Soochow University)

  • Zhaopei Guo

    (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences)

  • Jie Chen

    (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
    University of Science and Technology of China
    Jilin Biomedical Polymers Engineering Laboratory)

  • Lin Lin

    (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
    University of Science and Technology of China
    Jilin Biomedical Polymers Engineering Laboratory)

  • Yingying Hu

    (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
    University of Science and Technology of China
    Jilin Biomedical Polymers Engineering Laboratory)

  • Yanhui Li

    (Changchun University of Science and Technology)

  • Huayu Tian

    (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
    University of Science and Technology of China
    Jilin Biomedical Polymers Engineering Laboratory)

  • Xuesi Chen

    (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
    University of Science and Technology of China
    Jilin Biomedical Polymers Engineering Laboratory)

Abstract

Immunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.

Suggested Citation

  • Huapan Fang & Zhaopei Guo & Jie Chen & Lin Lin & Yingying Hu & Yanhui Li & Huayu Tian & Xuesi Chen, 2021. "Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27078-x
    DOI: 10.1038/s41467-021-27078-x
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    References listed on IDEAS

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