Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Immunol Res. 2020 Jun;8(6):794-805. doi: 10.1158/2326-6066.CIR-19-0619. Epub 2020 Mar 25.
Clinical response rates after adoptive cell therapy (ACT) are highly correlated with 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 promoter region. This led to IL21-mediated pSTAT3 binding to the 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 and ). Our findings support the application of IL21 and HDACi for the generation of highly persistent T-cell populations that can augment the efficacy of adoptively transferred T cells.
过继细胞疗法 (ACT) 后的临床反应率与输注 T 细胞的持久性高度相关。然而，肿瘤部位存在的抗原特异性 T 细胞通常是分化良好的效应细胞，其持久性有限。具有自我更新能力的中央记忆 CD8 T 细胞是理想的 ACT 产品。我们在这里报告，暴露于组蛋白去乙酰化酶抑制剂 (HDACi) 和 IL21 可以将分化的人 CD8 T 细胞重新编程为中央记忆样 T 细胞。CD8 T 细胞的去分化是由启动子区域 H3 乙酰化和染色质可及性增加引发的。这导致 IL21 介导的 pSTAT3 与 区域结合，随后上调表面 CD28 和 CD62L（中央记忆 T 细胞的标志物）。重编程细胞对 IL2 和 IL15 的反应均增强了增殖能力，并且具有稳定的记忆相关转录特征（增加 和 ）。我们的研究结果支持应用 IL21 和 HDACi 来产生高度持久的 T 细胞群体，从而增强过继转移 T 细胞的疗效。
