Immuno-oncology

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Exhaustion-associated De Novo Dna Methylation Restrains pd-1 Blockade-mediated T-cell Rejuvenation

Friday, June 16
6:15 PM - 7:30 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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