Abstract 654: The epigenetic landscape of T cell exhaustion

Abstract

Abstract Exhausted T cells in cancer and chronic viral infection have distinctive patterns of gene expression, including sustained expression of the inhibitory receptor PD-1, but the regulation of gene expression in exhausted T cells is poorly understood. Here we define the accessible chromatin landscape in mouse and human exhausted CD8+ T cells and show that it is profoundly different from functional memory CD8+ T cells. Exhausted CD8+ T cells in a mouse model of chronic viral infection acquire an extensive, state-specific pattern of enhancers, which are organized into functional modules. One enhancer, -23.8kb from the Pdcd1 locus, is found only in exhausted T cells and other lymphocytes with sustained PD-1 expression. Genome editing shows it to be required for high PD-1 expression. Cas9-mediated in situ saturation mutagenesis of the enhancer pinpoints critical minimal sequences that correspond to bound transcription factor motifs for RAR, T-bet and Sox3 in exhausted CD8+ T cells. State-specific enhancer profiles identified in mouse exhausted CD8+ T cells are conserved in human exhausted antigen-specific CD8+ T cells responding to HIV and HCV infection. Detailed functional enhancer maps of T cell exhaustion reveal state-specific regulatory sequences and offer targets for genome editing that could alter gene expression preferentially in exhausted CD8+ T cells. Citation Format: Debattama Sen. The epigenetic landscape of T cell exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 654. doi:10.1158/1538-7445.AM2017-654