Developing enhanced immunotherapy using NKG2A knockout human pluripotent stem cell-derived NK cells
Yue Qin, Qi Cui, Guihua Sun, Jianfei Chao, Cheng Wang, Xianwei Chen, Peng Ye, Tao Zhou, Arjit Vijey Jeyachandran, Olivia Sun, Wei Liu, Shunyu Yao, Chance Palmer, Xuxiang Liu, Vaithilingaraja Arumugaswami, Wing C. Chan, Xiuli Wang, Yanhong Shi
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.