Developing enhanced immunotherapy using NKG2A knockout human pluripotent stem cell-derived NK cells
Cancer immunotherapy is gaining increasing attention. However, immune checkpoints are exploited by cancer cells to evade anti-tumor immunotherapy. Here, we knocked out NKG2A, an immune checkpoint expressed on natural killer (NK) cells, in human pluripotent stem cells (hPSCs) and differentiated these hPSCs into NK (PSC-NK) cells. We show that NKG2A knockout (KO) enhances the anti-tumor and anti-viral capabilities of PSC-NK cells. NKG2A KO endows PSC-NK cells with higher cytotoxicity against HLA-E-expressing glioblastoma (GBM) cells, leukemia cells, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells in vitro. The NKG2A KO PSC-NK cells also exerted potent anti-tumor activity in vivo, leading to substantially suppressed tumor progression and prolonged survival of tumor-bearing mice in a xenograft GBM mouse model. These findings underscore the potential of PSC-NK cells with immune checkpoint KO as a promising cell-based immunotherapy. The unlimited supply and ease of genetic engineering of hPSCs makes genetically engineered PSC-NK an attractive option for easily accessible "off-the-shelf" cancer immunotherapy.
Authors
- Xuxiang Liu (ORCID: https://orcid.org/0000-0002-1677-0814)
- Xiuli Wang (ORCID: https://orcid.org/0000-0001-5964-4327)
- Tao Zhou (ORCID: https://orcid.org/0000-0003-2219-6385)
- Guihua Sun (ORCID: https://orcid.org/0000-0001-7337-3543)
- Jianfei Chao
- Arjit Vijey Jeyachandran
- Shunyu Yao
- Vaithilingaraja Arumugaswami (ORCID: https://orcid.org/0000-0002-6872-5118)
- Olivia Sun (ORCID: https://orcid.org/0009-0009-4011-0750)
- Wei Liu (ORCID: https://orcid.org/0000-0003-0004-2713)
- Yanhong Shi (ORCID: https://orcid.org/0000-0002-3938-5839)
- Yue Qin (ORCID: https://orcid.org/0000-0003-4277-3602)
- Peng Ye (ORCID: https://orcid.org/0000-0002-8327-2241)
- Cheng Wang (ORCID: https://orcid.org/0000-0001-6075-2878)
- Qi Cui (ORCID: https://orcid.org/0009-0009-5054-5221)
- Wing C. Chan (ORCID: https://orcid.org/0000-0002-1067-8216)
- Xianwei Chen (ORCID: https://orcid.org/0000-0002-4552-9851)
- Chance Palmer
Institutions
- City Of Hope National Medical Center (US)
- City of Hope (US)
- Broad Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-23
- DOI
- https://doi.org/10.1016/j.celrep.2024.114867
- Citations
- 16
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.85
Funders
- California Institute for Regenerative Medicine
- California Institute of Regenerative Medicine
- National Institutes of Health
- National Cancer Institute