DNA methylation of key genomic regions in murine T cells during chronic viral infection and in tumor models establishes stable gene-silencing that leads to terminal exhaustion of CD8+ T cells, restricting response to PD-L1 blockade. Administration of demethylating agents prior to PD-L1 blockade in Tramp-C2 mice increased proliferation of CD8+ TIL and improved tumor control.
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. 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, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T cell exhaustion and barrier of ICB-mediated T cell rejuvenation.
Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (2) Department of Computational Biology, St. Jude Children's Research Hospital, Memphis
Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (2) Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (3) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (4) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (5) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (6) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (7) Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (8) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (9) Hartwell Center for Bioinformatics & Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (10) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (11) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: benjamin.youngblood@stjude.org.
