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

CD8-Positive T-Lymphocytes / immunology Animals Clonal Hematopoiesis Epigenesis, Genetic Mice Humans Dioxygenases Immunotherapy DNA Methyltransferase 3A Repressor Proteins / genetics DNA-Binding Proteins / genetics Proto-Oncogene Proteins / metabolism DNA (Cytosine-5-)-Methyltransferases / genetics Cell Differentiation Immune Checkpoint Inhibitors / therapeutic use Histones / metabolism B7-H1 Antigen / metabolism

Journal

Science (New York, N.Y.)

ISSN: 1095-9203

Titre abrégé: Science

Pays: United States

ID NLM: 0404511

Informations de publication

Date de publication:
11 Oct 2024

Historique:

medline: 11 10 2024

pubmed: 11 10 2024

entrez: 10 10 2024

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1126/science.adl4492 PMID: 39388542

pubmed: 39388542

doi: 10.1126/science.adl4492

doi:

Substances chimiques

Dioxygenases EC 1.13.11.-

DNA Methyltransferase 3A EC 2.1.1.37

Repressor Proteins 0

DNA-Binding Proteins 0

Proto-Oncogene Proteins 0

Dnmt3a protein, mouse 0

Tet2 protein, mouse EC 1.13.11.-

DNA (Cytosine-5-)-Methyltransferases EC 2.1.1.37

Immune Checkpoint Inhibitors 0

Histones 0

DNMT3A protein, human 0

ASXL1 protein, human 0

TET2 protein, human EC 1.13.11.-

B7-H1 Antigen 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

eadl4492

Commentaires et corrections

Type : CommentIn