期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27078-x
关键词
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资金
- National Natural Science Foundation of China [51925305, 51873208, 51833010, 51973217, 51803210]
- National Science and Technology Major Projects for Major New Drugs Innovation and Development [2018ZX09711003-012]
- Jilin Province Science and Technology Development Program [20200201075JC]
While immunotherapy has shown promise as a cancer treatment, durable benefits are often limited by immune escape mechanisms. This study combines epigenetic regulation with gene therapy for immune checkpoint blockade to enhance anti-tumor effects and immune responses in vivo, providing a potential strategy for tumor treatment and prevention of relapse and metastasis.
While immunotherapy is a promising cancer treatment option, durable benefits are often rare due to immune escape. Here, the authors combine epigenetic regulation with gene therapy-mediated immune checkpoint blockade and show efficient anti-tumour effects and immune response in vivo. 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.
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