ligand gated Together the epigenetic interplay revealed in t

Together, the epigenetic interplay revealed in this study enabled us to expand the therapeutic potential of EZH2is from hematological malignances to solid tumors. In solid tumors, EZH2i-driven transcriptional changes are shown to be dispensable of H3K27me-regulated transcriptional network. Instead, MLL1/p300-dependent H3K27ac is essential to determine the ultimate and context-dependent transcriptional output. Of note, blockage of H3K27ac in this context could generate a cell-growth dependency to the MAPK pathway via transcriptional suppression of ERK1 (Figure 7A). These insights reveal that EZH2i caused the crosstalk between H3K27me and H3K27ac and leads to oncogene activation. This may suggest that targeting this crosstalk could provide therapeutic promise. Accordingly, patients with EZH2 overexpression could be stratified into three subtypes for EZH2-based therapy, namely EZH2 mono-therapy, its combination with BRD4 inhibitors or p300 inhibitors, and a triple combination plus MAPK pathway inhibitors. In the clinical practice, a step-up combination guided by the intrinsic MLL1 expression and subsequent feedback activation of ERK is proposed (Figure 7B). Our findings provide a possible solution for proper patient stratification based on the MLL1-directed combination therapy for EZH2 aberrant patients that can be rapidly translated to clinical tests. The recent disappointing result of tazemetostat as mono-therapy in treating EZH2 mutant DLBCL patients (NCT01897571) also highlights the need for rational integration of combination therapy and concurrent development of biomarkers to identify possible responders, which may expand the translational avenue for EZH2is in cancer treatments.
STAR★Methods
Acknowledgments
Introduction Chimeric antigen receptors (CARs) are recombinant proteins that link antibody-derived antigen-binding domains to stimulatory T cell-signaling pathways. Expressed in immune ligand gated cells, they induce activation responses to surface-expressed tumor target antigens, resulting in antigen-specific tumor cytolysis. T cells engineered to express CARs against the B lineage antigen CD19 are active to induce and maintain remissions in refractory B cell precursor leukemias2, 3, 4 and lymphomas.5, 6 The development of CAR T cells for solid tumors is limited by the paucity of target antigens reliably expressed at high densities on cancer cells, but not normal cells. We seek to develop cellular therapies to treat Ewing sarcoma (EwS), an aggressive solid mesenchymal malignancy arising in bone and soft tissues. EwS is characterized by a specific chromosomal translocation, most commonly of chromosomes 22 and 11 (t(11,22)(q24;12)), resulting in the aberrant chimeric transcription factor EWSR1-FLI1. Our group and others have shown that EwS can express the disialoganglioside GD2 on the cell surface.9, 10 GD2 expression characterizes immature neuroectodermal cells, with restricted and low-level tissue expression after birth on neuronal cells in the CNS, peripheral nerves, and mesenchymal stroma cells (MSCs)11, 12 (reviewed in Rossig et al.). GD2 was first evaluated as a therapeutic target in neuroblastoma, a cancer with abundant GD2 surface expression due to its tissue origin from neuroectoderm.14, 15 In early clinical studies, adoptive transfer of GD2-specific CAR T cells to neuroblastoma patients was safe with the first evidence of clinical activity (K. Straathof et al. 2018, AACR Cancer Res. abstract).16, 17, 18 Preclinical data support the use of GD2-specific CARs also for immunotherapy of EwS;10, 19, 20 however, only a proportion of EwS express GD2 at high levels,9, 19 which reduces the number of patients amenable to GD2-targeted therapies. Another limitation is the heterogeneity of GD2 antigen expression among tumor cells in individual EwS. Since effective CAR T cell-mediated cytolysis relies on high target densities,21, 22 GD2-low (GD2low) or GD2-negative (GD2neg) subpopulations escape CAR T cell targeting.