Fig. 2

Left: As cancer cells proliferate and tumors progress, T cell receptors become chronically stimulated, lose their effector functions, and become exhausted. Middle: In contrast to immunotherapies, the administration of epitherapies alters the gene expression of T cells. Epitherapy may “level the playing field” between cancer and immune cells by reducing tumor aggression through reprogramming of cancer stem cells from the mesenchymal to the epithelial phenotype. Additionally, epitherapies prime different subsets of exhausted T cells to better respond to immunotherapy. Different classes of epigenetic therapy have distinct transcriptional roles in resetting the epigenome. Right: Once primed by epitherapies and treated with monoclonal antibodies, such as blockade to the PD-1/PD-L1 pathway, T cells have optimal capacity for reinvigoration long term