Department of Molecular Biology and Immunology, Institute of Basic Medicine, Chinese People's Liberation Army General Hospital, Beijing, China.
Department of Bio-therapeutic, the First Medical Centre, Chinese People's Liberation Army General Hospital, Beijing, China.
Nat Commun. 2021 Jan 18;12(1):409. doi: 10.1038/s41467-020-20696-x.
Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor approved for clinical use, may provide a means of modifying exhaustion-associated DNA methylation programmes. Herein, anti-tumour activities, cytokine production, and proliferation are enhanced in decitabine-treated chimeric antigen receptor T (dCAR T) cells both in vitro and in vivo. Additionally, dCAR T cells can eradicate bulky tumours at a low-dose and establish effective recall responses upon tumour rechallenge. Antigen-expressing tumour cells trigger higher expression levels of memory-, proliferation- and cytokine production-associated genes in dCAR T cells. Tumour-infiltrating dCAR T cells retain a relatively high expression of memory-related genes and low expression of exhaustion-related genes in vivo. In vitro administration of decitabine may represent an option for the generation of CAR T cells with improved anti-tumour properties.
在癌症免疫疗法失败的特征中，T 细胞的根除能力不足和功能障碍是常见现象。新的 DNA 甲基化促进 T 细胞衰竭，而甲基化抑制则增强体内 T 细胞的再生。地西他滨是一种已被批准用于临床的 DNA 甲基转移酶抑制剂，可能为修饰与衰竭相关的 DNA 甲基化程序提供一种手段。在此，地西他滨处理的嵌合抗原受体 T（dCAR T）细胞在体外和体内均增强了抗肿瘤活性、细胞因子产生和增殖。此外，dCAR T 细胞可以在低剂量下消除大肿瘤，并在肿瘤再挑战时建立有效的回忆反应。表达抗原的肿瘤细胞在 dCAR T 细胞中触发更高水平的记忆、增殖和细胞因子产生相关基因的表达。在体内，肿瘤浸润的 dCAR T 细胞保留相对较高的记忆相关基因表达和较低的衰竭相关基因表达。体外给予地西他滨可能是一种选择，用于生成具有改善的抗肿瘤特性的 CAR T 细胞。
