Abstract A26: De novo epigenetic programming restrains PD-1 blockade-mediated T cell rejuvenation

Immune checkpoint blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. 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. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells. Therapeutic approaches to reverse these programs can enhance ICB-mediated T cell rejuvenation and ultimately facilitate the control of chronic viral infections and tumor growth. These data establish de novo DNA methylation programming as a regulator of T cell exhaustion and barrier of ICB therapy. Citation Format: Hazem E. Ghoneim, Yiping Fan, Ardiana Moustaki, Hossam Abdelsamed, Pradyot Dash, Pranay Dogra, Robert Carter, Walid Awad, Geoff Neale, Paul G. Thomas, Ben Youngblood. De novo epigenetic programming restrains PD-1 blockade-mediated T cell rejuvenation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A26.