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. In this study, 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.