Fig. 2

Epigenetic regulation of immune cells in the tumor microenvironment. Decreased KLF4 and increased SATB1 expression affect IL-6 (upregulation) and Galectin (downregulation) expression, remodeling anti-tumor DCs into pro-tumor DCs. MDSCs expansion, accumulation and recruitment are favored by STAT3-induced expression of immunosuppressive factors S100A8, Arg1 and S100A9. In this cell population, STAT3 expression is controlled by DNMTT3a/b, HDAC6 and HDAC11. Macrophages can convert into TAMs under the influence of multiple epigenetic factors, including DNMT3b, PRMT1, HDAC3/4, HDAC9 and SIRT2, favoring acquisition of the M2 phenotype through various pathways, such as increased PPARγ and Arg1 expression as well as downregulation of inflammatory factors TNF-α and IL-1β. SMYD3 activates M2 marker ALOX15. Impaired NK-cell anti-tumor cytotoxicity can be the result of increased EZH2 expression, which downregulates activating NK-cell receptor NKG2D through enhanced H3K27me3 levels. The same way, EZH2 also regulates inhibition of regulatory T-cell pro-inflammatory activities. Naïve CD8 + T-cells differentiate into TILs or exhausted CD8 + cells dependent on epigenetic profile. Whereas specific DNA methylation patterns of CTLA4, PDCD1 and LAG3 are identified in exhausted CD8 + T-cells, DNMT1 and EZH2 inhibit CD8 + TILs infiltration through downregulation of CXCL9 and CXCL10 chemokines. TGF-β and SATB1 affect TILs infiltration by controlling PD-1 expression. DCs, dendritic cells; MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; NK, natural killer; Tregs, regulatory T-cells; TILs, tumor-infiltrating lymphocytes