Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8+ T Cells to Memory T Cells.
Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8+ T Cells to Memory T Cells.
复制标题
组蛋白脱乙酰酶抑制剂和 IL21 协同将人类效应 CD8 T 细胞重编程为记忆 T 细胞。
DOI：
10.1158/2326-6066.cir-19-0619
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发表时间：
2020
影响因子：
10.1
通讯作者：
Yee,Cassian
中科院分区：
文献类型：
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作者：
Wang,Junmei;Hasan,Farah;Frey,AmandaC;Li,HaiyanS;Park,Jungsun;Pan,Ke;Haymaker,Cara;Bernatchez,Chantale;Lee,DeanA;Watowich,StephanieS;Yee,Cassian
过继性细胞治疗（ACT）后的临床应答率与输注T细胞的生存期高度相关。然而，在肿瘤部位发现的抗原特异性T细胞通常是具有有限持久性的分化良好的效应细胞。能够自我更新的中央记忆CD8+T细胞代表了理想的ACT产物。我们在这里报告，暴露于组蛋白去乙酰化酶抑制剂（HDACi）和IL 21可以重编程分化的人CD8+T细胞成中央记忆样T细胞。CD8+T细胞的去分化是由CD28启动子区域H3乙酰化和染色质可及性的增加启动的。这导致IL 21介导的pSTAT3与CD28区域结合，随后上调表面CD28和CD62L（中央记忆T细胞的标志物）。重编程的细胞表现出对IL 2和IL 15的反应增强的增殖，以及稳定的记忆相关转录特征（增加的Lef1和Tcf7）。我们的研究结果支持应用IL 21和HDACi体外产生高度持久的T细胞群，可以增强过继转移的T细胞的功效。
Clinical response rates after adoptive cell therapy (ACT) are highly correlated within vivopersistence of the infused T cells. However, antigen-specific T cells found in tumor sites are often well-differentiated effector cells with limited persistence. Central memory CD8+T cells, capable of self-renewal, represent desirable ACT products. We report here that exposure to a histone deacetylase inhibitor (HDACi) and IL21 could reprogram differentiated human CD8+T cells into central memory–like T cells. Dedifferentiation of CD8+T cells was initiated by increased H3 acetylation and chromatin accessibility at theCD28promoter region. This led to IL21-mediated pSTAT3 binding to theCD28region, and subsequent upregulation of surface CD28 and CD62L (markers of central memory T cells). The reprogrammed cells exhibited enhanced proliferation in response to both IL2 and IL15, and a stable memory-associated transcriptional signature (increasedLef1andTcf7). Our findings support the application of IL21 and HDACi for thein vitrogeneration of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.