한빛사논문
Tae Gun Kang 1, Xin Lan 1,2, Tian Mi 1, Hongfeng Chen 1, Shanta Alli 1, Song-Eun Lim 2,3, Sheetal Bhatara 3, Anoop Babu Vasandan 1, Grace Ward 1, Sofia Bentivegna 4,5, Josh Jang 6, Marianne L Spatz 7, Jin-Hwan Han 7, Balthasar Clemens Schlotmann 8, Jakob Schmidt Jespersen 5, Christopher Derenzo 9, Peter Vogel 10, Jiyang Yu 3, Stephen Baylin 11, Peter Jones 6, Casey O'Connell 12, Kirsten Grønbæk 4,5,13, Ben Youngblood 1*, Caitlin C Zebley 1,9*
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN 38105, USA.
3Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4Department of Hematology, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
5Biotech Research and Innovation Center (BRIC), University of Copenhagen, DK-2200 Copenhagen, Denmark.
6Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
7Merck & Co. Inc., Rahway, NJ 07065, USA.
8The Finsen Laboratory, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.
9Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
10Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
11Department of Oncology, The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins, Baltimore, MD 21231, USA.
12Jane Anne Nohl Division of Hematology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
13Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
*Corresponding authors: B.Y., C.C.Z.
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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