Fig. 2

Leveraging inhibition of epigenetic mechanisms to improve immunotherapy. DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi) and an inhibitor of histone methylation on histone H3 at lysine 27 (EZH2i) activate immunomodulatory mechanisms that may improve immunotherapy by: (i) increasing gene expression and activation of antigen presentation mechanisms; (ii) increasing gene expression of tumor-associated antigens such as cancer testis antigens (CTAs) MAGE and NY-ESO-1; (iii) upregulating inflammatory genes and pathways that rebalance the secretion of interferons (IFNs), cytokine and chemokines from tumor cells including the expression of normally silent endogenous retroviruses RNAs (EVRs) that activate the interferon response; (iv) upregulating targets of immune checkpoint blockade such as PD-1/PD-1L on both tumors and lymphocytes; and (v) activating the effector T cell population by promoting differentiation of naïve T cells to cytotoxic T cells and inhibiting T cell exhaustion mechanisms