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Ben A Youngblood, Hazem Ghoniem, Ardiana Moustaki, Hossam Aly Abdelsamed, Yiping Fan, Paul G Thomas, Sara Federico, Elizabeth Stewart, De novo DNA methylation programs restrain T cell rejuvenation during immune checkpoint blockade therapy, The Journal of Immunology, Volume 200, Issue Supplement_1, May 2018, Page 57.21, https://doi.org/10.4049/jimmunol.200.Supp.57.21
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Abstract
Immune-checkpoint blockade (ICB)-mediated rejuvenation of CD8 T cell effector functions has emerged as one of the most promising frontiers for treating cancer and chronic infections. However, antigen-specific T cells that have experienced prolonged antigen exposure are often terminally differentiated, and have a limited capacity to mount an effector response during ICB treatment. Such exhaustion of effector potential is a major impediment of current T cell based immunotherapy efforts. Using in vivo mouse models of tumor and chronic viral infection, we assessed the role of de novo epigenetic programming in establishing ICB-refractory exhausted T cells. We observed that genetic deletion of Dnmt3a in T cells at the effector stage of an immune response to chronic lymphocytic choriomeningitis virus (LCMV) infection allowed antigen-specific T cells to remain highly functional despite expressing high levels of PD-1 and having prolonged exposure to antigen. Quite strikingly, PD-1 blockade treatment of chronically infected animals resulted in massive expansion of PD-1+ Dnmt3a-deficient antigen-specific T cells. Whole-genome methylation profiling of WT and Dnmt3a-deficient LCMV-specific CD8 T cells identified de novo DNA methylation programs that are coupled to development of ICB-nonresponsive virus and tumor-specific T cells. Building upon these findings, we have identified de novo epigenetic programs acquired in human tumor-associated PD-1hi CD8 T cells. Collectively, these data establish Dnmt3a-mediated de novo DNA methylation programming as a key regulator in establishing ICB-refractory exhausted CD8 T cells and highlights epigenetic reprogramming of T cells as a novel approach to enhance T cell-based cancer therapies.
