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

Huapan Fang, Zhaopei Guo, Jie Chen, Lin Lin, Yingying Hu, Yanhui Li (), Huayu Tian () and Xuesi Chen
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Huapan Fang: Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
Zhaopei Guo: Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
Jie Chen: Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
Lin Lin: Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
Yingying Hu: Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
Yanhui Li: Changchun University of Science and Technology
Huayu Tian: Changchun Institute of Applied Chemistry, Chinese Academy of Sciences
Xuesi Chen: Changchun Institute of Applied Chemistry, Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27078-x

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