De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation.
De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation.
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从头表观遗传程序抑制PD-1封锁介导的T细胞再生。
DOI：
10.1016/j.cell.2017.06.007
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发表时间：
2017-06-29
期刊：
影响因子：
64.5
通讯作者：
Youngblood B
中科院分区：
文献类型：
--
作者：
Ghoneim HE;Fan Y;Moustaki A;Abdelsamed HA;Dash P;Dogra P;Carter R;Awad W;Neale G;Thomas PG;Youngblood B
免疫检查点阻断（ICB）介导的衰竭T细胞的再生已经成为治疗各种癌症和慢性感染的一种有前途的方法。然而，在长时间的抗原暴露期间变得完全耗尽的T细胞对ICB介导的再生仍然是难治的。我们报告说，阻断活化的CD 8 T细胞中的从头DNA甲基化使它们能够保留其效应功能，尽管在持续的病毒感染期间受到慢性刺激。在免疫应答的效应阶段和耗竭阶段对抗原特异性鼠CD 8 T细胞进行全基因组亚硫酸氢盐测序，确定了在PD-1阻断治疗期间限制T细胞扩增和克隆多样性的渐进性获得性可遗传的从头甲基化程序。此外，这些耗竭相关的DNA甲基化程序在肿瘤浸润性PD-1hi CD 8 T细胞中获得，并且逆转这些程序的方法改善了ICB期间的T细胞应答和肿瘤控制。这些数据建立了从头DNA甲基化编程作为T细胞耗竭的调节剂和ICB介导的T细胞再生的屏障。从头DNA甲基化程序促进T细胞耗竭，阻断这些程序可以增强T细胞再生，通过免疫检查点阻断来帮助肿瘤控制。
Immune-checkpoint blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T-cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T-cell exhaustion and barrier of ICB-mediated T-cell rejuvenation. de novo DNA methylation programs promote T-cell exhaustion, and blocking these programs can enhance T cell rejuvenation, aiding tumor control by immune checkpoint blockade.
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在单细胞水平上表观遗传调节的动力学。
DOI：
10.1126/science.aab2956
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bintu L;Yong J;Antebi YE;McCue K;Kazuki Y;Uno N;Oshimura M;Elowitz MB
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影响因子：
64.8
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Ahmed R
DOI：
10.1007/978-1-4939-2963-4_15
发表时间：
2015-01-01
期刊：
IMMUNOSENESCENCE: METHODS AND PROTOCOLS
影响因子：
--
作者：
Dash, Pradyot;Wang, George C.;Thomas, Paul G.
通讯作者：
Thomas, Paul G.
影响因子：
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Ahuja N
影响因子：
11.2
作者：
Curran MA;Allison JP
通讯作者：
Allison JP