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1.	Tan, SY, et al. (author) Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity 2021 In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 218:9 Journal article (peer-reviewed)abstract 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.

Tan, SY, et al. (author)
Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity
2021
In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 218:9
Journal article (peer-reviewed)abstract
- 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.

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