DataSheet_1_EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells.pdf

Enhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of agents targeting costimulatory receptors is not known. Here, we explore the combination between EZH2i and an agonist antibody targeting the T cell costimulatory receptor 4-1BB (α4-1BB). Our data show that EZH2i compromise the efficacy of α4-1BB in both CT26 colon carcinoma and in an in vivo protein immunization model. We link this to reduced effector survival and increased BIM expression in CD8+ T cells upon EZH2i treatment. These data support the requirement of EZH2 function in 4-1BB-mediated CD8+ T cell expansion and effector programming and emphasize the consideration that must be given when combining such antitumoral therapies.

Enhancer of Zeste Homolog 2（EZH2）抑制剂（EZH2i）已被批准用于治疗某些类型的癌症。先前的研究表明，将EZH2i与针对共抑制性受体如PD-(L)1和CTLA-4的免疫检查点阻断相结合的潜力，但尚不清楚其是否也能增强针对共刺激受体的治疗剂的活性。在本研究中，我们探讨了EZH2i与靶向T细胞共刺激受体4-1BB（α4-1BB）的激动性抗体的联合应用。我们的数据显示，EZH2i会降低α4-1BB在CT26结肠癌和体内蛋白质免疫模型中的疗效。我们将此与EZH2i治疗后CD8+ T细胞效应器存活减少和BIM表达增加联系起来。这些数据支持了EZH2功能在4-1BB介导的CD8+ T细胞扩增和效应器编程中的必要性，并强调了在联合此类抗肿瘤疗法时必须给予的考虑。