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Updated: Jun 9, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Developing enhanced immunotherapy using NKG2A knockout human pluripotent stem cell-derived NK cells
Yue Qin1, Qi Cui1, Guihua Sun1
1Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA.
Abstract:
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.
Insights
Genetically modifying natural killer (NK) cells by knocking out the NKG2A immune checkpoint significantly boosts their ability to fight cancer and viral infections. These enhanced NK cells show potent anti-tumor effects in preclinical models.
Area of Science:
- Immunology
- Cell Therapy
- Cancer Research
Background:
- Cancer immunotherapy faces challenges as cancer cells exploit immune checkpoints to evade treatment.
- Natural killer (NK) cells are crucial for innate immunity against tumors and viruses.
- NKG2A is an inhibitory immune checkpoint receptor expressed on NK cells.
Purpose of the Study:
- To investigate the therapeutic potential of genetically engineered human pluripotent stem cell-derived NK (PSC-NK) cells lacking NKG2A.
- To evaluate the enhanced anti-tumor and anti-viral functions of NKG2A-knockout (KO) PSC-NK cells.
Main Methods:
- NKG2A was knocked out in human pluripotent stem cells (hPSCs).
- hPSCs were differentiated into NK (PSC-NK) cells.
- In vitro and in vivo assays were performed to assess cytotoxicity against cancer cells and virus-infected cells, and anti-tumor efficacy in a glioblastoma mouse model.
Main Results:
- NKG2A knockout significantly enhanced the cytotoxicity of PSC-NK cells against HLA-E-expressing glioblastoma (GBM) and leukemia cells.
- NKG2A KO PSC-NK cells demonstrated increased efficacy against SARS-CoV-2-infected cells in vitro.
- In vivo studies showed potent anti-tumor activity, suppressing tumor progression and prolonging survival in a GBM xenograft mouse model.
Conclusions:
- NKG2A knockout in PSC-NK cells represents a promising strategy for enhancing cell-based cancer immunotherapy.
- Genetically engineered PSC-NK cells offer a potential source of readily available, 'off-the-shelf' immunotherapies due to their unlimited supply and ease of genetic modification.
