The maturation and functional competence of natural killer (NK) cells is a tightly controlled process that relies on transcription factors (TFs). Here, we identify transcriptional repressor zinc fingers and homeoboxes 2 (Zhx2) as a novel regulator that restricts NK cell maturation and function. Mice with Zhx2 conditional deletion in NK cells (Zhx2Δ/Δ) showed accumulation of matured NK cells. Loss of Zhx2 enhanced NK cell survival and NK cell response to IL-15. Transcriptomic analysis revealed Zeb2, a key TF in NK cell terminal maturation, as a direct downstream target of Zhx2. Therapeutically, transfer of Zhx2-deficient NK cells resulted in inhibition of tumor growth and metastasis in different murine models. Our findings collectively unmask a previously unrecognized role of Zhx2 as a novel negative regulator in NK cell maturation and highlight its therapeutic potential as a promising strategy to enhance NK cell–mediated tumor surveillance.
Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity
Disclosures: The authors declare no competing interests exist.
- Award Id(s): 81830017,81902433,81902051
- Award Id(s): 81425012
- Award Id(s): tspd20181201
- Award Id(s): 2018YFJH0503
- Award Id(s): 2018YFE0126500
- Views Icon Views
- Share Icon Share
- Search Site
Siyu Tan, Xiaowei Guo, Mengzhen Li, Tixiao Wang, Zehua Wang, Chunyang Li, Zhuanchang Wu, Nailin Li, Lifen Gao, Xiaohong Liang, Chunhong Ma; Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity. J Exp Med 6 September 2021; 218 (9): e20210009. doi: https://doi.org/10.1084/jem.20210009
Download citation file: