Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-10-11 DOI:10.1126/science.adl4492

Tae Gun Kang, Xin Lan, Tian Mi, Hongfeng Chen, Shanta Alli, Song-Eun Lim, Sheetal Bhatara, Anoop Babu Vasandan, Grace Ward, Sofia Bentivegna, Josh Jang, Marianne L. Spatz, Jin-Hwan Han, Balthasar Clemens Schlotmann, Jakob Schmidt Jespersen, Christopher Derenzo, Peter Vogel, Jiyang Yu, Stephen Baylin, Peter Jones, Casey O’Connell, Kirsten Grønbæk, Ben Youngblood, Caitlin C. Zebley

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引用次数: 0

Abstract

Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group–repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti–PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.

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克隆造血的表观遗传调节因子在免疫疗法中控制 CD8 T 细胞干性。

众所周知，T细胞衰竭的表观遗传强化是限制免疫疗法中T细胞反应的主要障碍。然而，在长期抗原暴露过程中限制抗肿瘤免疫的核心表观遗传调节因子尚不清楚。我们研究了三种促进克隆造血的常见突变表观遗传调节因子，以确定它们是否会影响T细胞的干性和对检查点阻断免疫疗法的反应。缺乏Dnmt3a、Tet2或Asxl1的CD8 T细胞在慢性抗原暴露期间保留了祖细胞耗竭（Tpex）群体1年以上，而没有发生恶性转化。Asxl1控制了T细胞的自我更新能力，并通过H2AK119泛素化和多聚酶组抑制性去泛素化酶途径的表观遗传修饰减少了CD8 T细胞的分化。Asxl1缺陷T细胞与抗PD-L1免疫疗法协同作用，改善了实验模型中的肿瘤控制，并使接受治疗的患者的突变T细胞具有生存优势。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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