EZH1/EZH2 Inhibition Enhances Adoptive T-cell Immunotherapy Against Multiple Cancer Models

Tumor resistance to chimeric antigen receptor T-cell (CART) therapy is a major challenge. Epigenetic modulation, which rewires cancer cells to a more immunogenic phenotype, could improve adoptive T cell (ACT) efficacy. This study hypothesized that inhibiting EZH2 would enhance ACT. In Germinal Center-derived B-cell human lymphoma models, EZH2 inhibition with tazemetostat improved anti-CD19 CART (CART19) tumor control. The goal of this experiment is to test is tazemetostat-treated tumors showed chromatin opening at genes related to cell-cell adhesion, B-cell activation, and inflammatory responses. Overall design: To understand the role of EZH2 in shaping the chromatin accessibility of tumor cells in response to CART19 treatment, a diffuse large B-cell Lymphoma derived cell line (SUDHL4-GFP+) was pre-treated with the EZH2 inhibitor tazemetostat or a vehicle control. The cell lines were subsequently exposed to either untransduced (UTD) T cells or CART19. The tumor cells were then sorted from the T cells and processed for assay for transposase-accessible chromatin (ATAC-seq).