Ezh2 in NK cell functional regulation
Improving the function of immune cells in tumor microenvironment remains a major challenge in cancer treatment. EZH2 serves as the catalytic subunit of PRC2 that mediates gene repression via catalyzing H3K27me3 at specific genetic loci. Many studies have provided evidence showing that the tumor cell-intrinsic mechanisms of Ezh2-driven oncogenesis and tumor progression. However, the function of EZH2 in tumorigenesis by regulating the tumor immune microenvironment remains poorly understood. Here we used Cre-ERT2/Ezh2fl/fl mouse model to investigate the function and molecular mechanism of Ezh2 in tumor immune microenvironment. Tamoxifen-induced deletion of Ezh2 before tumor cells inoculation resulted in reduced tumor growth and lung metastasis in different tumor xenograft models. Neutralizing natural killer (NK) cells function by anti-NK1.1 antibody completely blocked Ezh2-KO-caused tumor repressive effect. To investigate the mechanism by which EZH2 modulates NK cell function, we profiled >4000 mouse lung NK cells using single-cell RNA sequencing to produce a comprehensive transcriptional landscape and compared WT or Ezh2-/- NK cells development, fate decision and function. We found that deletion of Ezh2 significantly promotes the maturity and function of NK cell. Mechanistically, Ezh2 deletion upregulated the expression of genes related to NK cell maturation and adhesion to tumor cells through reprograming chromatin architecture. Our findings suggest that EZH2 depletion will elevate the tumor-killing of NK cells, which may provide an alternative strategy for cancer immune therapy. Overall design: ChIP-seq, ATAC-seq, Hi-C and RNA-seq for bone marrow (BM)-induced NK cells from Ezh2-/- and WT mice.