Abstract 473: Inhibition of SUMOylation reverses T-cell metabolic exhaustion in large B-cell lymphoma

Abstract Immune based therapies for large B cell lymphoma (LBCL) have transformed our approach to this disease. Therapies such as CD3 bispecific T cell engagers and chimeric antigen receptor (CAR) T cells, have diverse mechanisms of action, yet they all depend on activation of T cells to affect an anti-cancer response. While the often-dramatic responses seen to immune therapies have captured wide-spread attention, the majority of patients treated with immune based therapies for relapsed lymphoma will not achieve long term cure, and poor T cell function is a common mechanism for treatment failure. Several seminal studies have identified T-cell metabolic reprogramming as a key mechanism behind T-cell exhaustion. Mechanisms to reverse metabolic exhaustion and reinvigorate T-cells has been shown to lead to increased anti-tumor responses. Small ubiquitin-like modifiers (SUMO) proteins regulate a variety of cellular processes in tumor and immune cells. Inhibitors of SUMOylation (SUMOi) have shown anti-tumor activity in a CD8 T-cell dependent manner, however, the mechanism behind this T-cell dependence is unknown. We show that a novel covalent SUMOi, SB-4826 leads to a robust anti-tumor response which is dependent on CD8+ T-cells in lymphoma. Using single cell metabolic studies, we demonstrate that SUMOi increases the metabolic rate, glycolytic dependency and proliferative capacity of tumor infiltrating PD1+ CD8+ T cells. We further show that SUMOylation is increased following T-cell activation, and exhausted CD8+ TILs have the highest levels of total SUMOylation of T-cell subsets. We validate these findings of increased SUMOylation in CD8+ TILs in human lymphoma samples. In a CD19 CAR T-cell model, we show that pulse treatment of CAR T-cells with SUMOi leads to enhanced anti-lymphoma activity in vitro. Using a mass-spectroscopy/immunoprecipitation approach, we identified more than 1, 000 proteins which are SUMOylated in T-cells. We found that multiple T-cell transcriptional regulators, including TBET, LEF1 and TCF1 are all SUMOylated either during a resting or activation state in CD8+ T-cells. Together, these findings suggest a novel role for SUMOylation in regulating T-cell effector activation and exhaustion, by modulating metabolic state likely through the regulation of key transcriptional T-cell programs. Citation Format: Joseph Lownik, Larry Milshteyn, Anton Villamejor, Akil Merchant. Inhibition of SUMOylation reverses T-cell metabolic exhaustion in large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 473.