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

被引：25

作者：

Kang, Tae Gun ^{[1
]}

Lan, Xin ^{[1
,2
]}

Mi, Tian ^{[1
]}

Chen, Hongfeng ^{[1
]}

Alli, Shanta ^{[1
]}

Lim, Song-Eun ^{[2
,3
]}

Bhatara, Sheetal ^{[3
]}

Vasandan, Anoop Babu ^{[1
]}

Ward, Grace ^{[1
]}

Bentivegna, Sofia ^{[4
,5
]}

Jang, Josh ^{[6
]}

Spatz, Marianne L. ^{[7
]}

Han, Jin-Hwan ^{[7
]}

Schlotmann, Balthasar Clemens ^{[8
]}

Jespersen, Jakob Schmidt ^{[5
]}

Derenzo, Christopher ^{[9
]}

Vogel, Peter ^{[10
]}

Yu, Jiyang ^{[3
]}

Baylin, Stephen ^{[11
]}

Jones, Peter ^{[6
]}

O'Connell, Casey ^{[12
]}

Gronbaek, Kirsten ^{[4
,5
,13
]}

Youngblood, Ben ^{[1
]}

Zebley, Caitlin C. ^{[1
,9
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[2] Univ Tennessee, Hlth Sci Ctr, Coll Grad Hlth Sci, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA

[4] Copenhagen Univ Hosp, Dept Hematol, Rigshosp, DK-2100 Copenhagen, Denmark

[5] Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark

[6] Van Andel Inst, Dept Epigenet, Grand Rapids, MI 49503 USA

[7] Merck & Co Inc, Rahway, NJ 07065 USA

[8] Univ Copenhagen Hosp, Finsen Lab, Rigshosp, DK-2100 Copenhagen, Denmark

[9] St Jude Childrens Res Hosp, Dept Bone Marrow Transplantat & Cellular Therapy, Memphis, TN 38105 USA

[10] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[11] Sidney Kimmel Comprehens Canc Johns Hopkins, Dept Oncol, Baltimore, MD 21231 USA

[12] Univ Southern Calif, Keck Sch Med, Dept Med, Jane Anne Nohl Div Hematol, Los Angeles, CA 90033 USA

[13] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark

来源：

SCIENCE | 2024年 / 386卷 / 6718期

基金：

美国国家卫生研究院;

关键词：

TERMINAL DIFFERENTIATION; INFECTION; SUBSET; PD-1;

D O I：

10.1126/science.adl4492

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页数：15

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