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

• 成果类型: Article
• 署名作者: Kang, Tae Gun; Lan, Xin; Mi, Tian; Chen, Hongfeng; Alli, Shanta; Lim, Song-Eun; Bhatara, Sheetal; Vasandan, Anoop Babu; Ward, Grace; Bentivegna, Sofia; Jang, Josh; Spatz, Marianne L.; Han, Jin-Hwan; Schlotmann, Balthasar Clemens; Jespersen, Jakob Schmidt; Derenzo, Christopher; Vogel, Peter; Yu, Jiyang; Baylin, Stephen; Jones, Peter; O'Connell, Casey; Gronbaek, Kirsten; Youngblood, Ben; Zebley, Caitlin C.
• 署名单位: St Jude Children's Research Hospital; University of Tennessee System; University of Tennessee Health Science Center; St Jude Children's Research Hospital; University of Copenhagen; Copenhagen University Hospital; Rigshospitalet; University of Copenhagen; Van Andel Institute; Merck & Company; Merck & Company USA; Rigshospitalet; University of Copenhagen; Copenhagen University Hospital; St Jude Children's Research Hospital; St Jude Children's Research Hospital; Johns Hopkins University; Johns Hopkins Medicine; University of Southern California; University of Copenhagen
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10954
• DOI: 10.1126/science.adl4492
• 发表日期: 2024-10-01
• 关键词: terminal differentiation; infection; subset; pd-1

摘要

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.