EZH2 regulatory roles in cancer immunity and immunotherapy

Enhancer of zeste homolog 2 (EZH2) is a polycomb repressor complex 2 (PRC2) subunit that is responsible for silencing expression of target genes through generation of lysine 27 trimethylation on histone H3 (H3K27Me3). EZH2 is an oncogene aberrantly expressed in human cancers, and its overexpression favors immune escape and metastasis. Immune escape occurs via the impact of EZH2 on hampering antigen expression machinery, stabilizing FOXP3 in regulatory T cells (Tregs), inhibiting recruitment and activity of natural killer (NK) and CD8⁺ T cells, and inducing recruitment and activity of myeloid-derived suppressor cells (MDSCs). Besides, EZH2 also promotes intra-tumoral recruitment of tumor-associated macrophages (TAMs). A point is that pharmacologic EZH2 inhibition (not knockdown) seemingly promotes polarization of macrophages toward pro-tumor M2 phenotype, which defines resistance mechanism. Besides, increased EZH2 expression after anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and a rise in the tumoral expression of programmed death-ligand 1 (PD-L1) after EZH2 inhibition account for secondary immunosuppression in tumor ecosystem after immunotherapy, indicating the applicability of using EZH2 targeted therapies as a combinatory approach with anti-programmed death-1 (PD-1) or anti-CTLA-4 therapy. Such combination reinvigorates anti-tumor immunity and presumably hampers T cell exhaustion and acting as a promising regimen for retarding cancer growth.