ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion

CD8+ T cell exhaustion limits the immune response to tumors because of ineffective T cell effector functions. Thus, therapies that inhibit T-cell exhaustion are critical for optimizing cancer treatment. Recent studies have implicated epigenetic proteins in T-cell exhaustion. Here, we identified activating transcription factor 7 interacting protein (ATF7ip) as an epigenetic protein critical for inducing T cell exhaustion. Loss of Atf7ip in CD8+ T cells resulted in decreased terminal exhaustion and increased numbers of progenitor-exhausted cells in both chronic viral infections and cancer. Given the decreased T cell terminal exhaustion observed with Atf7ip-deficiency in CD8+ T cells, this may be one mechanism that leads to decreased tumor burden. Mechanistically, ATF7ip functions to stimulate the deposition of repressive H3K9me3 at critical immune-effector gene loci, such as Il7r and Il2 leading to enhanced exhaustion. Our data suggest that ATF7ip may be a rational target for deletion in adoptive T-cell therapies to reduce CD8+ T-cell exhaustion.