Bromodomain protein BRD4 directs CD8 T cell differentiation during infection and cancer

Abstract In response to infection and malignancy, antigen-specific CD8 T cells differentiate into functionally diverse populations that are critical for resolving disease and providing durable immunity. Here, we utilized an in vivo RNAi screening strategy to identify transcriptional and epigenetic regulators controlling CD8 T cell fate. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we revealed an essential role for the chromatin modifier and BET family member BRD4 in supporting T cell differentiation during infection and cancer. BRD4 was found to bind diverse regulatory regions critical to effector T cell differentiation and was essential for transcriptional activity of terminal effector-specific super-enhancers in vivo. Consequentially, induced deletion or chemical inhibition of BRD4 resulted in impaired maintenance of a terminal effector phenotype. In preclinical models of cancer, BRD4 was also required for formation of a terminally differentiated CD8 T cell state in the tumor microenvironment, which we show holds implications for immunotherapies. Tailored inhibition of BRD4 enhanced immune checkpoint blockade efficacy; however, complete ablation of BRD4 activity blunted T cell effector function and adoptive cell therapy efficacy. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis-regulatory elements to control CD8 T cell fate and stability of lineage identity, and provide insight for understanding the efficacy and full therapeutic potential of BET inhibition and T cell immunotherapies.