Tumor infiltrating T cells acquire exhaustion-associated epigenetic programs

Abstract

Abstract Antigen-specific CD8 T cells play a critical role in controlling chronic infections and cancer, but progressively lose their effector functions during prolonged antigen exposure. Repression of CD8 T cell effector functions, commonly referred to as T cell exhaustion, limits the ability of the immune system to purge the chronic pathogen from the host. It has recently become recognized that CD8 T cell exhaustion programs can be reinforced and heritably maintained. Therefore in order to develop and/or improve current therapeutic approaches that utilize host antigen-specific T cells to treat chronic infections or cancer a major challenge for the field is to identify mechanisms that stabilize T cell exhaustion. Using the LCMV model system of chronic viral infection we determined that Dnmt3a mediated de novo DNA methylation plays a causal role in establishing CD8 T cell exhaustion. We then performed whole-genome methylation profiling of WT and Dnmt3a cKO CD8 T cells from chronically infected animals and identified Dnmt3a-dependent DNA methylation programs in genes, including interferon gamma and Tcf7, that are coupled to the progressive decline in effector function and developmental plasticity of the antigen specific cell. Lastly, we extended these findings to the tumor setting using a syngeneic mouse tumor model. We found that tumor-infiltrating PD-1hi CD8 T cells acquire exhaustion-associated de novo DNA methylation programs. These results have significant implications for therapeutic strategies that utilize reactivation of host pathogen-specific CD8 T cells to control chronic viral infections or cancer and provide a nucleotide-resolution map of epigenetic programs progressively acquired during T cell exhaustion.