T-cell lymphoma (TCL) is a rare subtype of non-Hodgkin lymphoma (NHL) that is associated with a poor prognosis. Although HDAC inhibitors have been approved for TCL treatment for several years, their expected therapeutic efficacy remains unmet in some patients. In this study, we discovered that TCL tumor cells develop resistance to HDAC inhibitor treatment by upregulating the methylation of lysine 27 on histone H3 (H3K27me3) levels. Furthermore, we confirmed the pharmacological efficacy of the EZH2 inhibitor SHR2554 and demonstrated a synergistic effect when combined with the HDAC inhibitor Chidamide through commercial TCL cell lines, in vivo cell-derived xenograft, and patient-derived xenograft cancer models. We inferred that STAT1 was the key driver of the synergistic effect using RNA-seq and ChIP-seq analysis. Our findings provide sufficient preclinical evidence in support of a potential combination therapy strategy for TCL patients.

Germinal center (GC) is the vital locus for the evolution of naïve B cells into memory B and plasma cells, but also a hotbed for the proliferation of malignant B cells. We hypothesized that malignant B cells may locally or globally impact GCs to produce peripheral B cell receptor immune repertoire (BCR IR) with reduced clonal diversity. In this study, we first validated our hypothesis in a novel human in-vitro GC (hiGC) model. The addition of the diffuse large B cell lymphoma (DLBCL) cells to the hiGC culture attenuated the rate of diversity growth. For clinical validation, we collected samples from 17 DLBCL patients at various points during high-dose therapy and autologous stem cell rescue. The elimination and reestablishment of the patients’ lymphatic pool allowed us to unambiguously monitor the impact of tumor cells on the replenishment of the peripheral BCR IR. Compared to the nine patients who did not relapse after treatment, relapsed patients tended to have a slower rate of recovery regarding the clonal diversity of their peripheral BCR IR. Our results suggest a mechanistic and clinical connection between residual tumor cells and abnormal peripheral BCR IR, which may corelate with treatment efficacy in B cell lymphomas.