In vivo gene editing of T-cells in lymph nodes for enhanced cancer immunotherapy
Immune checkpoint blockade (ICB) therapy, while promising for cancer treatment, faces challenges like unexpected side effects and limited objective responses. Here, we develop an in vivo gene-editing strategy for improving ICB cancer therapy in a lastingly effective manner. The approach uses a conductive hydrogel-based electroporation system to enable nucleofection of programmed cell death protein 1 (PD1) targeted CRISPR-Cas9 DNAs into T-cells directly within the lymph nodes, and subsequently produces PD1-deficient T-cells to combat tumor growth, metastasis and recurrence in different melanoma models in mice. Following in vivo gene editing, animals show enhanced cellular and humoral immune responses along with multi-fold increases of effector T-cells infiltration to the solid tumors, preventing tumor recurrence and prolonging their survival. These findings provide a proof-of-concept for direct in vivo T-cell engineering via localized gene-editing for enhanced cancer immunotherapy, and also unlock the possibilities of using this method to treat more complex human diseases.
Authors
- Weibin Jia (ORCID: https://orcid.org/0000-0001-5532-7199)
- Cheuk Yin Li (ORCID: https://orcid.org/0000-0002-9109-385X)
- Zixun Wang (ORCID: https://orcid.org/0000-0003-0252-2737)
- Wei Li (ORCID: https://orcid.org/0000-0002-9339-7267)
- Peng Shi (ORCID: https://orcid.org/0000-0003-0629-4161)
- Mingxue Wang
- Chuxiao Xiong (ORCID: https://orcid.org/0000-0003-4240-7266)
- Yuan Wang (ORCID: https://orcid.org/0000-0002-7355-9505)
- Jin Qu (ORCID: https://orcid.org/0009-0002-5968-1069)
- Xingdao He (ORCID: https://orcid.org/0000-0002-3068-9131)
- Tianlong Zhang (ORCID: https://orcid.org/0009-0004-6174-9055)
- B Kuang
Institutions
- Department of Health (CN)
- City University of Hong Kong (HK)
- Chinese Academy of Sciences (CN)
- Hong Kong University of Science and Technology (HK)
- Wuhan University (CN)
- Suzhou Institute of Nano-tech and Nano-bionics (CN)
- City University of Hong Kong, Shenzhen Research Institute (CN)
- Zhongnan Hospital of Wuhan University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1038/s41467-024-54292-0
- Citations
- 16
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 4.52
Funders
- City University of Hong Kong
- National Natural Science Foundation of China
- Innovation and Technology Commission