Hematopathologist Cedars-Sinai Med. Ctr., California, United States
Introduction/Rationale: Immune checkpoint inhibitors (ICI) targeting PD1 have revolutionized our approach to solid tumors and Hodgkin lymphoma, but they have not been effective in treating Large B Cell Lymphoma (LBCL). Recent therapeutic options, including bispecific antibodies, have proven effective in a subset of LBCL patients, but are still ineffective in a subset of patients. Multiple studies have demonstrated that T-cell exhaustion is a primary mechanism of resistance to immunotherapies, including in lymphoma. Therefore, novel mechanisms to address T-cell exhaustion are required to improve outcomes with these therapies. Here, we demonstrate the role of the post-translational process of SUMOylation in regulating CD8 T-cell exhaustion in the lymphoma microenvironment.
Methods: The A20 syngeneic LBCL model murine studies. Additionally, patient derived lymphoid organoids (PDLOs) were used to model the effect of SUMOylation in human lymphoma. Highly mutliplexed spatial imaging was performed to evaluate the role of SUMOylation in T-cells in the TME of lymphoma patients.
Results: In the A20 model, exhausted CD8 T-cells had the highest levels of SUMOylation compared to other T-cell subsets. Inhibiting SUMOylation resulted in increased metabolic activity and increased utilization of oxidative phosphorylation for ATP production. Additionally, inhibiting SUMOylation in PDLO samples resulted in improved response to bispecific therapy in a subset of patients which were initially non-responsive to bispecific antibodies, which corresponded with improved metabolic activity. Additionally, T-cells from patients had higher SUMOylation levels in more aggressive lymphomas compared to indolent lymphomas, and correlated with in vitro response to bispecific antibodies.
Conclusion: Here, we demonstrate that inhibition of SUMOylation results in significant reprogramming of CD8 T-cell metabolic activity in both mouse and human models. This metabolic reprogramming of CD8 T-cells sensitizes tumors to immunotherapies, for improved outcomes.
