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- W4313365762 abstract "Abstract T cell-based immunotherapies have emerged as one of the most promising frontiers in the fight against cancer and chronic infections. However, it has become clear that prolonged exposure of T cells to their cognate antigen drives them toward a terminally differentiated state, limiting their capacity to mount an effector response. The commitment of T cells to this “exhausted” fate is currently a major barrier in the advancement of T cell immunotherapy efforts. To better understand mechanisms that reinforce the T cell exhaustion gene expression program, we investigated the role of de novo epigenetic programming in establishing exhausted T cells that are non-responsive during immune checkpoint blockade (ICB) therapy. Using mouse models of tumor and chronic viral infection, we observed that genetic deletion of the de novo DNA methyltransferase, Dnmt3a, in antigen-specific T cells that are chronically stimulated allowed them to remain highly functional despite expressing high levels of the checkpoint inhibitory receptor PD-1. Furthermore, PD-1 blockade treatment resulted in massive expansion of PD-1+ Dnmt3a-deficient antigen-specific T cells. Building upon the findings from our murine studies, we have generated whole-genome DNA methylation profiles of human CD8 T cells from a wide array of differentiation states, and established an epigenetic-based human T cell multipotency index. Using this index, we report that tumor-associated PD-1hi CD8 T cells from pediatric solid tumors acquire an epigenetically reinforced terminal differentiation program. Collectively, these data establish Dnmt3a-mediated de novo DNA methylation programming as a key factor in limiting CD8 T cell-based immunotherapuetic approaches." @default.
- W4313365762 created "2023-01-06" @default.
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- W4313365762 date "2019-05-01" @default.
- W4313365762 modified "2023-09-26" @default.
- W4313365762 title "De novo DNA methylation programs regulate T cell exhaustion and limit T cell-based immunotherapies" @default.
- W4313365762 doi "https://doi.org/10.4049/jimmunol.202.supp.134.14" @default.
- W4313365762 hasPublicationYear "2019" @default.
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