BRD4 and BET proteins regulate CD8 T cell exhaustion in mouse models of cancer

Abstract

Abstract Harnessing the cytotoxic capacity of CD8 T cells is central to the efficacy of immunotherapy and has revolutionized the fight against cancer. However, despite encouraging success for select indications, immunotherapies still fail to achieve durable and effective outcomes for certain cancer types and in many patients. Failure of immunotherapies often results from CD8 T cells differentiating into an epigenetically controlled and reinforced state known as T cell exhaustion. Therefore, resolving the molecular programs governing T cell differentiation within the tumor microenvironment (TME) is critical to enhancing treatment. Using mouse models of breast cancer and pancreatic cancer, we investigated the role of the bromodomain and extraterminal (BET) family of proteins in mediating T cell differentiation and exhaustion. Depletion of BRD2, BRD3, and BRD4 in CD8 T cells differentially affected CD8 T cell accumulation and the exhausted phenotype within the tumor microenvironment. Further, small molecule inhibition of the BET family similarly impacted CD8 T cell differentiation and exhaustion in vivo. Our findings may inform new strategies to circumvent CD8 T cell exhaustion during infection. supported by a training grant from the UNC Pharmacology Department (5T32GM135095-02)