Decitabine-Mediated Epigenetic Reprograming Enhances Anti-leukemia Efficacy of CD123-Targeted Chimeric Antigen Receptor T-Cells
Decitabine-Mediated Epigenetic Reprograming Enhances Anti-leukemia Efficacy of CD123-Targeted Chimeric Antigen Receptor T-Cells
复制标题
地西他滨介导的表观遗传重编程增强 CD123 靶向嵌合抗原受体 T 细胞的抗白血病功效。
DOI：
10.3389/fimmu.2020.01787
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发表时间：
2020-08-18
影响因子：
7.3
通讯作者：
Qian, Wenbin
中科院分区：
文献类型：
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作者：
You, Liangshun;Han, Qingmei;Qian, Wenbin
嵌合抗原受体（CAR）T细胞代表了晚期血液癌症患者的潜在治愈性疗法;然而，围绕细胞内在适应性以及限制CAR-T能力的耗竭的不确定性。地西他滨（DAC）是一种DNA去甲基化剂，已被证明可以逆转耗竭相关的DNA甲基化程序，并改善T细胞对肿瘤的反应。在这里，我们表明DAC在体外和体内显著增强CD 123 CAR-T细胞的抗白血病功能。此外，它还抑制DMNT 3a和DNMT 1的表达。使用Illumina甲基化EPIC BeadChip（850 K），我们鉴定了差异甲基化区域，其中大部分经历低甲基化变化。转录组学分析显示，用DAC处理的CD 123 CAR-T细胞富集了与幼稚、早期记忆T细胞以及非耗竭T细胞相关的基因。DAC治疗还导致免疫突触相关基因的上调。最后，我们的数据进一步表明，DAC的工作通过调节细胞分化的幼稚和记忆表型的特点。总之，这些发现表明DAC改善了CD 123导向的CAR-T细胞的抗白血病特性，并为急性髓性白血病（AML）患者的合理组合CAR-T免疫治疗提供了基础。
Chimeric antigen receptor (CAR) T cells represent a potentially curative therapy for patients with advanced hematological cancers; however, uncertainties surround the cell-intrinsic fitness as well as the exhaustion that restrict the capacity of CAR-T. Decitabine (DAC), a DNA demethylating agent, has been demonstrated to reverse exhaustion-associated DNA-methylation programs and to improve T cell responses against tumors. Here we show that DAC significantly enhances antileukemia functions of CD123 CAR-T cellsin vitroandin vivo. Additionally, it inhibits the expression of DMNT3a and DNMT1. Using the Illumina Methylation EPIC BeadChip (850 K), we identified differentially methylated regions, most of which undergo hypomethylated changes. Transcriptomic profiling revealed that CD123 CAR-T cells treated with DAC were enriched in genes associated with naive, early memory T cells, as well as non-exhausted T cells. DAC treatment also results in upregulation of immune synapse-related genes. Finally, our data further suggest that DAC works through the regulation of cellular differentiation characterized by naive and memory phenotypes. Taken together, these findings demonstrate that DAC improves the anti-leukemia properties of CD123-directed CAR-T cells, and provides a basis for rational combinatorial CAR-T-based immunotherapy for patients with acute myeloid leukemia (AML).