Cancer Cell | 抑制EZH2可诱导淋巴瘤免疫原性并改善T细胞功能，从而增强T细胞免疫疗法的效果 (康奈尔大学)

    Somatic gain-of-function mutations of the histone methyltransferase EZH2, frequently observed in germinal center B cell (GCB) subtype of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), enhance the conversion of H3K27me2 to H3K27me3, a histone mark associated with repression of transcription. 

    Retrospective studies showed that the molecular subtype of DLBCL C3/EZB, typically featuring EZH2 mutations and BCL2 translocation, experienced inferior outcomes following CAR-T therapy. EZH2 is required for the formation and maintenance of germinal centers (GCs). GC B cells compete for TFH cell help, based on the affinity of their B cell receptor for antigen, and those that fail to receive help undergo apoptosis. Only a few receiving T cell help are selected to exit the GC and form antibody-secreting plasma cells. EZH2 mutations initiate lymphomagenesis by silencing genes critical for immune synapse signaling, reducing GC B cell dependency on T cell help. In established lymphomas, EZH2 promotes immune evasion by silencing MHC expression, hindering tumor-T cell interactions. Preclinical studies demonstrated the potent efficacy of EZH2 inhibitors (such as tazemetostat) against DLBCL and FL, derived from GC B cells, regardless of EZH2 mutation status. EZH2 inhibition restores MHC-I and MHC-II expression in EZH2-mutant DLBCL cell lines. EZH2 not only controls the epigenetic and transcriptional program within GC B cells and GC-derived lymphomas but also regulates the TME. EZH2 governs Treg maintenance, Teff cell expansion, and suppresses memory-related transcription factors in CD8+ T cells (TCF7, BACH2, and EOMES). Therefore, researchers explored how EZH2 inhibition directly affects T and CAR-T cells, assessing potential deleterious effects.

    Here, researchers explored how EZH2 inhibitors work in lymphoma patients with relatively intact immune systems. EZH2 inhibitors have antiproliferative effects on lymphoma cells but can also recruit T cells into lymphomas in mice, though it is not known if these T cells have any functional consequence or tumoricidal activity. They found that EZH2 inhibition didn’t influence lymphoma proliferation and viability, but enhanced T-cell mediated killing ability. Transcription analysis showed that there was a significant upregulation of costimulatory receptors and ligands triggered by EZH2 inhibition, so they hypothesized that EZH2 inhibitors can restore lymphoma B-T interactions beyond MHC dependence. Strikingly, tazemetostat pretreatment resulted in significant reduction of cognate lymphoma cells viability regardless of the presence of MHC-I blocking antibody, indicating EZH2 inhibition restored lymphoma B-T interactions beyond MHC dependence. Since T cell infiltration, activation, and interaction with lymphoma cells is critical for the efficacy of cellular immunotherapy, they further evaluated the combination of EZH2 inhibitor tazemetostat with CD20×CD3 T cell engaging bispecific antibody or CD19 CAR-T cells (CAR-T19).  The combined treatment of EZH2 inhibitors well enhances the sensitivity of lymphomas to T-cell immunotherapy, both in mouse and humanized models. Moreover, EZH2 inhibition on lymphoma cells improves CAR-T recruitment, interaction quality and killing activity without detrimental effects. Their results also show that EZH2 inhibition improved long-term CAR-T19 killing activity by facilitating a memory CD8 phenotype and therefore preventing exhaustion. At last, they further explored the effect of EZH2 inhibition on human patients, and found that administering tazemetostat to patients before immunotherapy may enhance lymphoma immunogenicity and potentially improve CAR-T activity and TME remodeling from an immunosuppressive to immunocompetent state by reducing Tregs without harming T cells.