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  3. CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8(+) T Cell-Relevant Genes

CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8(+) T Cell-Relevant Genes

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Aznar, MA
  • Labiano, S
  • Diaz-Lagares, A
  • Molina, C
  • Garasa, S
  • Azpilikueta, A
  • Etxeberria, I
  • Sanchez-Paulete, AR
  • Korman, AJ
  • Esteller, M
  • Melero, I

Grupos

Abstract

CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA methylation arrays were carried out on human peripheral blood CD8(+) T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors. CD96, HHLA2, CCR5, CXCR5, and CCL5 were among the immune-related genes regulated by differential DNA methylation, leading to changes in mRNA and protein expression. These genes are also differentially methylated in naive versus antigen-experienced CD8(+) T cells. The transcription factor TCF1 and the microRNA miR-21 were regulated by DNA methylation upon CD137 costimulation. Such gene-expression regulatory factors can, in turn, broaden the effects of DNA methylation by controlling expression of their target genes. Overall, chromatin remodeling is postulated to leave CD137-costimulated T lymphocytes poised to differentially respond upon subsequent antigen recognition. Accordingly, CD137 connects costimulation during priming to genome-wide DNA methylation and chromatin reprogramming. (C) 2017 AACR.

Datos de la publicación

ISSN/ISSNe:
2326-6066, 2326-6074

Cancer Immunology Research  AMER ASSOC CANCER RESEARCH

Tipo:
Article
Páginas:
69-78
PubMed:
29133290
Factor de Impacto:
4,990 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 42

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Keywords

  • CANCER-IMMUNOTHERAPY; VIRAL-INFECTION; MONOCLONAL-ANTIBODIES; EFFECTOR FUNCTION; TUMOR-IMMUNITY; MEMORY; EXPRESSION; ACTIVATION; SIGNALS; TARGET

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