期刊
CELL DEATH & DISEASE
卷 11, 期 11, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-020-03187-1
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资金
- National Special Research Program of China for Important Infectious Diseases [2018ZX10302103, 2017ZX10202102]
- Important Key Program of the Natural Science Foundation of China [81730060]
- International Collaboration Program of the Natural Science Foundation of China [81561128007]
- U.S. NIH [81561128007]
- Joint-Innovation Program in Healthcare for Special Scientific Research Projects of Guangzhou [201803040002]
- Guangdong Basic and Applied Basic Research Foundation [2019A1515010882]
Long-lived plasma cells (LLPCs) are robust specialized antibody-secreting cells that mainly stay in the bone marrow and can persist a lifetime. As they can be generated by inducing the differentiation of B-lymphocytes, we investigated the possibility that human LLPCs might be engineered to express alpha -PD-1 monoclonal antibody to substitute recombinant alpha -PD-1 antitumor immunotherapy. To this end, we inserted an alpha -PD-1 cassette into the GAPDH locus through Cas9/sgRNA-guided specific integration in B-lymphocytes, which was mediated by an integrase-defective lentiviral vector. The edited B cells were capable of differentiating into LLPCs both in vitro and in vivo. Transcriptional profiling analysis confirmed that these cells were typical LLPCs. Importantly, these cells secreted de novo antibodies persistently, which were able to inhibit human melanoma growth via an antibody-mediated checkpoint blockade in xenograft-tumor mice. Our work suggests that the engineered LLPCs may be utilized as a vehicle to constantly produce special antibodies for long-term cellular immunotherapy to eradicate tumors and cellular reservoirs for various pathogens including human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV).
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