Abstract NG04: Disrupting enhancers within the core epigenetic program of exhaustion improves CD8+ T cell responses and enhances tumor control

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-07, Vol.81 (13_Supplement), p.NG04-NG04
• Main Authors: Sen, Debattama, Weiss, Sarah A., Miller, Brian C., Yates, Kathleen B., Lafleur, Martin W., Sharpe, Arlene H., Haining, W. Nicholas
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2021-NG04

T cell exhaustion describes an acquired dysfunction common in settings of cancer and chronic viral infection. Despite clinical efforts to rescue exhaustion, the fundamental mechanisms specifying this state, and the potential for reprogramming exhausted T cells, remain poorly understood. We profiled accessible chromatin in chronic viral infection to show that exhausted CD8+ cells acquire a state-specific landscape of enhancers that profoundly differs from functional memory. By comparing antigen-specific T cells in several contexts of T cell dysfunction, we found that CD8+ tumor infiltrating lymphocytes share significant epigenetic and transcriptional features with chronic viral infection, highlighting that T cell exhaustion is a fundamental adaptation to settings of chronic stimulation. Critically, we identify a core epigenetic signature, independent of disease-specific milieu, that can act as a precise biomarker of the exhausted state. Comparison of mouse cells to those isolated from patients infected with HCV or HIV showed that the core epigenetic program of exhaustion is conserved across species. Importantly, curative therapy, which reduces viral antigen load, as well as checkpoint blockade immunotherapy, which reduces inhibitory T cell signaling, failed to reverse the exhausted epigenetic profile. T cell exhaustion is therefore a stable epigenetic state that is not rescued by common treatment modalities. We then sought new strategies to modulate T cell exhaustion. We identified a novel candidate enhancer near the PD-1 gene that is unique to exhausted CD8+ T cells and a component of the core epigenetic program. Using Cas9-mediated genome editing, we generated a novel mouse strain with germ-line deletion of this region to characterize the role of this enhancer in vivo. We observed 2-3-fold enrichment of PD-1 enhancer-null cells over control cells in chronic infection, suggesting that CD8+ T cells in these mice might be less prone to exhaustion. Importantly, PD-1 enhancer-null cells had increased persistence without any deficits in functionality as has been described with the full PD-1 gene knock-out. As a result, deletion of the PD-1 enhancer gave rise to significantly higher numbers of IFNg+ immunotherapy-responsive T cells compared to both WT and PD-1 gene ablation. These data suggest that deletion of a state-specific enhancer in immune cells can promote unique functional capacities from those observed with the full gene knock-out. Next, we wanted to un