Jeong Yurim, Jang Hyewon, Kim Se Been, Yu Minseo, Kim Ra Eun, Choi Wan-Su, Jeon Youngwoo, Lim Jung-Yeon
Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea.
Department of Hematology, Yeouido St. Mary Hospital, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Front Immunol. 2025 Apr 16;16:1578665. doi: 10.3389/fimmu.2025.1578665. eCollection 2025.
Enhancer of zeste homolog 2 (EZH2) catalyzes H3K27me3, an epigenetic modification linked to gene silencing, and its overexpression contributes to the progression of hematological malignancies. This study compares the efficacy of a conventional EZH2 inhibitor with a PROTAC-based EZH2 degrader in human lymphoma cell lines. Furthermore, we investigate the anti-tumor effects of combining EZH2 degrader with anti-PD-1, an immune checkpoint inhibitor, focusing on immune cell interactions and underlying mechanisms.
The cytotoxic effects of the EZH2 degrader and EZH2 inhibitor were evaluated in Burkitt's, B-cell, cutaneous T-cell, and Hodgkin's lymphoma cell lines. Additionally, the combination therapy of the EZH2 degrader and anti-PD-1 was assessed both and in a hu-PBMC-CDX mouse model.
We evaluated the effects of an EZH2 degrader on seven lymphoma cell lines and observed significant reductions in cell viability compared to EZH2 inhibitor, particularly in Burkitt's lymphoma cell lines. EZH2 degrader treatment reduced EZH2 and c-Myc expression, induced G2/M cell cycle arrest, and increased apoptosis markers, including cleaved caspase-3 and cleaved PARP. Furthermore, Burkitt's lymphoma is a PD-L1 negative tumor; however, treatment with the EZH2 degrader resulted in a slight increase in PD-L1 expression. Combining EZH2 degrader with anti-PD-1 significantly enhanced anti-tumor effects compared to monotherapy. studies using a humanized lymphoma mouse model demonstrated a synergistic anti-tumor effect of EZH2 degrader and anti-PD-1, which was attributed to apoptosis-related pathways.
These findings aim to provide insights into the therapeutic potential of targeting EZH2 in combination with immune checkpoint inhibitors for improved treatment of lymphomas.
zeste 同源物 2 增强子（EZH2）催化 H3K27me3，这是一种与基因沉默相关的表观遗传修饰，其过表达促进血液系统恶性肿瘤的进展。本研究比较了传统 EZH2 抑制剂与基于 PROTAC 的 EZH2 降解剂在人淋巴瘤细胞系中的疗效。此外，我们研究了将 EZH2 降解剂与免疫检查点抑制剂抗 PD-1 联合使用的抗肿瘤作用，重点关注免疫细胞相互作用及其潜在机制。
在伯基特淋巴瘤、B 细胞淋巴瘤、皮肤 T 细胞淋巴瘤和霍奇金淋巴瘤细胞系中评估 EZH2 降解剂和 EZH2 抑制剂的细胞毒性作用。此外，还在体外和人外周血单核细胞-人源化肿瘤异种移植（hu-PBMC-CDX）小鼠模型中评估了 EZH2 降解剂与抗 PD-1 的联合治疗效果。
我们评估了 EZH2 降解剂对七种淋巴瘤细胞系的作用，与 EZH2 抑制剂相比，观察到细胞活力显著降低，尤其是在伯基特淋巴瘤细胞系中。EZH2 降解剂处理降低了 EZH2 和 c-Myc 的表达，诱导 G2/M 期细胞周期阻滞，并增加了凋亡标志物的表达，包括裂解的半胱天冬酶-3 和裂解的聚（ADP-核糖）聚合酶。此外，伯基特淋巴瘤是一种 PD-L1 阴性肿瘤；然而，用 EZH2 降解剂处理导致 PD-L1 表达略有增加。与单一疗法相比，将 EZH2 降解剂与抗 PD-1 联合使用显著增强了抗肿瘤效果。使用人源化淋巴瘤小鼠模型的研究证明了 EZH2 降解剂和抗 PD-1 的协同抗肿瘤作用，这归因于凋亡相关途径。
这些发现旨在为联合免疫检查点抑制剂靶向 EZH2 改善淋巴瘤治疗的潜在治疗价值提供见解。
