Immuno-oncology

Thematic

Exhaustion-Associated De Novo DNA Methylation Restrains PD-1 Blockade-Mediated T-Cell Rejuvenation

Friday, June 16
1:25 PM - 1:40 PM

Immune-checkpoint blockade (ICB)-mediated rejuvenation of exhausted CD8 T cells has emerged as a promising frontier for treating cancer and chronic infections. However, antigen-specific T cells that have differentiated to a terminal state of exhaustion remain refractory to ICB-mediated rejuvenation and currently have limited potential for contributing to this promising therapeutic approach. Given that many of the impaired effector-properties of terminally exhausted CD8 T cells appear to be heritably maintained even in the absence of antigen, we investigated the role of de novo DNA-methylation programming as a cell-intrinsic mechanism for establishing the ICB-nonresponsive state of T-cell exhaustion. Combining whole-genome bisulfite sequencing with a TCR-inducible system to conditionally delete the de novo DNA methyltransferase, Dnmt3a, in recently activated CD8 T cells (cKO), we mapped genome-wide changes in epigenetic programming that regulate the progressive development of T cell exhaustion. PD-L1 blockade was unable to erase the exhaustion-associated de novo methylation programs in WT CD8 T cells and resulted in expansion of a clonally-restricted, functionally-stunted subset of T cells. In contrast, PD-L1 blockade treatment of chronically infected Dnmt3a cKO mice resulted in amplified expansion and retained TCR repertoire diversity of LCMV-specific T cells, that enhanced viral control. Extending our findings to the tumor setting, we confirmed that exhaustion-associated DNA methylation programs are acquired in tumor-infiltrating PD-1hi CD8 T cells. These data establish Dnmt3a as a critical regulator in the development of T-cell exhaustion, and the resulting de novo methylation programs as a primary and stable barrier of ICB-mediated T cell rejuvenation.

Hazem E. Ghoneim

Postdoctoral Research Associate
Department of Immunology, St. Jude Children's Research Hospital

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Yiping Fan

St. Jude Children's Research Hospital

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Ardiana Moustaki

St. Jude Children's Research Hospital

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Hossam Abdelsamed

St. Jude Children's Research Hospital

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Pradyot Dash

St. Jude Children's Research Hospital

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Pranay Dogra

St. Jude Children's Research Hospital

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Robert Carter

St. Jude Children's Research Hospital

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Walid Awad

St. Jude Children's Research Hospital

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Geoffrey Neale

Director, Hartwell Center for Bioinformatics and Biotechnology
St. Jude Children’s Research Hospital

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Paul Thomas

St. Jude Children's Research Hospital

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Ben Youngblood

Department of Immunology, St. Jude Children's Research Hospital

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Exhaustion-Associated De Novo DNA Methylation Restrains PD-1 Blockade-Mediated T-Cell Rejuvenation



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