Abstract A189: Targeting T-cell epigenetic programs to enhance the efficacy of immune checkpoint blockade

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 T-cell-intrinsic mechanism for establishing the ICB-nonresponsive state of T-cell exhaustion. 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 DNA methylation programs. Blocking de novo DNA methylation in activated CD8 T-cells allowed them to retain their effector functions despite persistent stimulation during chronic viral infection. We found that these de novo epigenetic programs are not only critical for establishing T-cell exhaustion, but also restrict T-cell expansion and clonal diversity during PD-L1 blockade treatment. Moreover, these exhaustion-associated DNA methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T-cell. Therapeutic approaches to reverse these programs enhanced antitumor CD8 T-cell responses and tumor control during PD-L1 blockade therapy. These data establish de novo DNA methylation programming as a major T-cell-intrinsic barrier of ICB therapy. Targeting T-cell epigenetic programs provides great potential for fostering more powerful T-cell immunotherapies. Reference: Ghoneim, et al. Cell 2017. Citation Format: Hazem E. Ghoneim, Yiping Fan, Ardiana Moustaki, Hossam Abdelsamed, Pradyot Dash, Pranay Dogra, Robert Carter, Walid Awad, Geoff Neale, Paul Thomas, Ben Youngblood. Targeting T-cell epigenetic programs to enhance the efficacy of immune checkpoint blockade [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A189.