2. Academic Validation
  3. Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity

Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity

  • J Exp Med. 2021 Sep 6;218(9):e20210009. doi: 10.1084/jem.20210009.
Siyu Tan 1,  Xiaowei Guo 1,  Mengzhen Li 1,  Tixiao Wang 1,  Zehua Wang 1,  Chunyang Li 2,  Zhuanchang Wu 1,  Nailin Li 3,  Lifen Gao 1 4,  Xiaohong Liang 1 4,  Chunhong Ma 1 5 4
Affiliations

Affiliations

  • 1 Key Laboratory for Experimental Teratology of the Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province, and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong, China.
  • 2 Key Laboratory for Experimental Teratology of the Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong, China.
  • 3 Clinical Pharmacology Group, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
  • 4 Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, Shandong, China.
  • 5 Advanced Medical Research Institute, Shandong University, Jinan, Shandong, China.
PMID: 34279541 DOI: 10.1084/jem.20210009
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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