Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy
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.
Authors
- Peter Vogel (ORCID: https://orcid.org/0000-0002-7535-0545)
- Caitlin C. Zebley (ORCID: https://orcid.org/0000-0002-8419-4660)
- Jakob Schmidt Jespersen (ORCID: https://orcid.org/0000-0002-4930-5900)
- Tae Gun Kang (ORCID: https://orcid.org/0000-0002-2997-9887)
- Kirsten Grønbæk (ORCID: https://orcid.org/0000-0002-1535-9601)
- Shanta Alli (ORCID: https://orcid.org/0000-0003-1692-1616)
- Balthasar Schlotmann (ORCID: https://orcid.org/0000-0002-8137-544X)
- Mi Tian (ORCID: https://orcid.org/0000-0002-6446-1995)
- Christopher DeRenzo (ORCID: https://orcid.org/0000-0001-6127-4601)
- Anoop Babu Vasandan
- Casey Lee O'Connell (ORCID: https://orcid.org/0000-0001-7665-3911)
- Ben Youngblood (ORCID: https://orcid.org/0000-0002-1261-9957)
- Stephen B. Baylin (ORCID: https://orcid.org/0000-0003-3697-3798)
- Marianne Spatz
- Grace Ward (ORCID: https://orcid.org/0000-0003-4404-7727)
- Sofía Bentivegna (ORCID: https://orcid.org/0009-0005-3824-0290)
- Peter A. Jones (ORCID: https://orcid.org/0000-0001-8309-4767)
- Sheetal Bhatara (ORCID: https://orcid.org/0009-0007-3597-6870)
- Xin Lan (ORCID: https://orcid.org/0009-0002-1031-0435)
- Jiyang Yu (ORCID: https://orcid.org/0000-0003-1244-4429)
- Hongfeng Chen (ORCID: https://orcid.org/0000-0002-0705-0946)
- Jin‐Hwan Han (ORCID: https://orcid.org/0000-0003-2442-8442)
- Song-Eun Lim
- Josh Jang
Institutions
- University of Southern California (US)
- University of Copenhagen (DK)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- St. Jude Children's Research Hospital (US)
- Van Andel Institute (US)
- University of Tennessee Health Science Center (US)
- Copenhagen University Hospital (DK)
- Rigshospitalet (DK)
- Sidney Kimmel Comprehensive Cancer Center (US)
Publication Details
- Journal
- Science
- Published
- 2024-10-10
- DOI
- https://doi.org/10.1126/science.adl4492
- Citations
- 71
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 17.08
Funders
- American Lebanese Syrian Associated Charities
- National Comprehensive Cancer Network
- National Institutes of Health
- Stand Up To Cancer