在体外膨胀过程中，tazemetostat暂时抑制EZH2，保持T细胞的茎状并改善生养T细胞疗法
Transient EZH2 Suppression by Tazemetostat during In Vitro Expansion Maintains T-Cell Stemness and Improves Adoptive T-Cell Therapy
影响因子:8.20000
分区:医学1区 Top / 免疫学2区 肿瘤学2区
发表日期:2025 Jan 09
作者:
Yingqin Hou, Jaroslav Zak, Yujie Shi, Isaraphorn Pratumchai, Brandon Dinner, Wenjian Wang, Ke Qin, Evan W Weber, John R Teijaro, Peng Wu
摘要
Zeste同源2（EZH2）的组蛋白甲基转移酶增强酶在T细胞分化，增殖和功能中起重要作用。先前的研究表明，CD8+或总T细胞中EZH2的遗传缺失会损害其抗病毒和抗肿瘤活性，细胞因子的产生以及扩展在弥补上的能力。与删除T细胞中的EZH2的有害作用相反，在这项研究中，我们证明，在用临床认可的抑制剂TazeMetostat（TAZ）（TAZ）的表型发作之前，T细胞对EZH2的瞬时抑制作用延迟了功能障碍的进展和保留的TCELLESTION和多funiffif，但延迟了延迟的TCELLIFES，但具有延迟的影响。 TAZ诱导的T细胞表观遗传重编程通过在快速分裂的T细胞中优先降低其启动子的H3K27甲基化，从而增加了自我更新T细胞转录因子TCF1的表达。在鼠类黑色素瘤模型中，EZH2耗尽的T细胞诱导肿瘤对照不良，而通过TAZ预处理的TAZ预处理的T细胞表现出优异的抗肿瘤免疫力，尤其是与抗PD-1结合结合使用时。总的来说，这些数据突出了EZH2抑制瞬时表观遗传重编程的潜力，从而增强了收养T细胞免疫疗法。
Abstract
The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T-cell differentiation, proliferation, and function. Previous studies have demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activities, cytokine production, and ability to expand upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, in this study, we demonstrated that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, tazemetostat (Taz), delayed their dysfunctional progression and preserved T-cell stemness and polyfunctionality but had no negative impact on cell proliferation. Taz-induced T-cell epigenetic reprogramming increased the expression of the self-renewal T-cell transcription factor TCF1 by reducing H3K27 methylation at its promoter preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induced poor tumor control, whereas adoptively transferred T cells pretreated with Taz exhibited superior antitumor immunity, especially when used in combination with anti-PD-1 blockade. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T-cell immunotherapy.