Damele Laura, Amaro Adriana, Serio Alberto, Luchetti Silvia, Pfeffer Ulrich, Mingari Maria Cristina, Vitale Chiara
UO Immunologia IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.
UO Epigenetica dei Tumori IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.
Cancers (Basel). 2021 Jan 16;13(2):319. doi: 10.3390/cancers13020319.
The dysregulation of epigenetic modifications has a well-established role in the development and progression of hematological malignancies and of solid tumors. In this context, EZH1/2 inhibitors have been designed to interfere with EZH1/2 enzymes involved in histone methylation (e.g., H3K27me3), leading to tumor growth arrest or the restoration of tumor suppressor gene transcription. However, these compounds also affect normal hematopoiesis, interfering with self-renewal and differentiation of CD34-Hematopoietic Stem/Progenitor Cells (HSPC), and, in turn, could modulate the generation of potential anti-tumor effector lymphocytes. Given the important role of NK cells in the immune surveillance of tumors, it would be useful to understand whether epigenetic drugs can modulate NK cell differentiation and functional maturation. CD34-HSPC were cultured in the absence or in the presence of the EZH1/2 inhibitor UNC1999 and EZH2 inhibitor GSK126. Our results show that UNC1999 and GSK126 increased CD56 cell proliferation compared to the control condition. However, UNC1999 and GSK 126 favored the proliferation of no-cytotoxic CD56ILC3, according to the early expression of the AHR and ROR-γt transcription factors. Our results describe novel epigenetic mechanisms involved in the modulation of NK cell maturation that may provide new tools for designing NK cell-based immunotherapy.
表观遗传修饰的失调在血液系统恶性肿瘤和实体瘤的发生发展中具有明确作用。在此背景下，EZH1/2抑制剂被设计用于干扰参与组蛋白甲基化（如H3K27me3）的EZH1/2酶，从而导致肿瘤生长停滞或肿瘤抑制基因转录的恢复。然而，这些化合物也会影响正常造血，干扰CD34+造血干细胞/祖细胞（HSPC）的自我更新和分化，进而可能调节潜在抗肿瘤效应淋巴细胞的生成。鉴于自然杀伤（NK）细胞在肿瘤免疫监视中的重要作用，了解表观遗传药物是否能调节NK细胞分化和功能成熟将很有意义。将CD34+HSPC在不存在或存在EZH1/2抑制剂UNC1999和EZH-2抑制剂GSK126的情况下进行培养。我们的结果表明，与对照条件相比，UNC1999和GSK126增加了CD56+细胞的增殖。然而，根据芳香烃受体（AHR）和维甲酸相关孤儿受体γt（ROR-γt）转录因子的早期表达，UNC1999和GSK126有利于无细胞毒性的CD56+ILC3的增殖。我们的结果描述了参与调节NK细胞成熟的新表观遗传机制，这可能为设计基于NK细胞的免疫疗法提供新工具。
