Clinical response rates after adoptive cell therapy (ACT) are highly correlated with in vivo persistence 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 the CD28 promoter region. This led to IL21-mediated pSTAT3 binding to the CD28 region, 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 (increased Lef1 and Tcf7 ). Our findings support the application of IL21 and HDACi for the in vitro generation of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.

中文翻译：

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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。

过继细胞疗法 (ACT) 后的临床反应率与输注 T 细胞在体内的持久性高度相关。然而，在肿瘤部位发现的抗原特异性 T 细胞通常是分化良好的效应细胞，但持久性有限。具有自我更新能力的中央记忆 CD8+ T 细胞是理想的 ACT 产品。我们在此报告，暴露于组蛋白脱乙酰酶抑制剂 (HDACi) 和 IL21 可以将分化的人类 CD8+ T 细胞重新编程为中枢记忆样 T 细胞。CD8+ T 细胞的去分化是通过 CD28 启动子区域 H3 乙酰化和染色质可及性的增加而启动的。这导致 IL21 介导的 pSTAT3 与 CD28 区域结合，并随后上调表面 CD28 和 CD62L（中央记忆 T 细胞的标记）。重编程的细胞对 IL2 和 IL15 的反应表现出增强的增殖，以及稳定的记忆相关转录特征（Lef1 和 Tcf7 增加）。我们的研究结果支持应用 IL21 和 HDACi 在体外生成高度持久的 T 细胞群，从而增强过继转移 T 细胞的功效。