Histone methyltransferase Ezh2 negatively regulates NK cell terminal maturation and function

Area of Science:

• Immunology
• Cell Biology
• Epigenetics

Background:

• Natural killer (NK) cells are crucial innate immune cells for tumor eradication and viral clearance.
• Previous studies indicated that inhibiting enhancer of zeste homolog 2 (Ezh2) in hematopoietic stem and progenitor cells (HSPCs) boosts NK cell commitment and tumor cytotoxicity.

Purpose of the Study:

• To investigate the specific effects of Ezh2 inhibition on NK cell development and function, particularly within the NK lineage.
• To test the hypothesis that Ezh2 negatively regulates NK cell maturation and cytotoxic activity.

Main Methods:

• Utilized Ezh2^fl/fl and Ncr1^iCre mice to genetically delete Ezh2 in immature NK cells.
• Administered EZH2 inhibitors during human NK cell differentiation from HSPCs.
• Performed in vitro cytotoxicity assays, degranulation assays, IFN-γ production measurements, RNA-sequencing, and CUT&RUN-qPCR.

Main Results:

• Ezh2 deficiency in mice led to increased NK cell numbers and promoted terminal differentiation, evidenced by higher percentages of mature CD27^- CD11b⁺ subsets.
• Inhibition of EZH2 in human NK cell differentiation increased mature NK cell proportions and enhanced cytotoxicity.
• Ezh2 was found to directly modulate the expression of the transcription factor Pbx1, a known promoter of NK cell development.

Conclusions:

• Enhancer of zeste homolog 2 (Ezh2) acts as a negative regulator of NK cell terminal maturation and function.
• Targeting Ezh2 may represent a therapeutic strategy to enhance NK cell-mediated anti-tumor immunity.