IMMU-08. Metabolic reprogramming of CD8+ T-Cells by DPP-4 inhibition for glioblastoma immunotherapy

Abstract Glioblastoma (GBM) is characterized by T cell exclusion and exhaustion. Therefore, there is a pressing need to identify molecular targets for improved T cell response in GBM. We recently showed that FDA-approved dipeptidyl peptidase-4 (DPP-4) inhibitors, which are used for clinical management of type II diabetes, mediate an immune-dependent anti-GBM response. However, the function of DPP-4 in immune regulation and cancer remains poorly defined. We observed that DPP-4 is highly expressed by CD8+ T cells infiltrating brain tumors, and its expression levels increase with the exhaustion or memory differentiation of mouse and human effector T cells. Pharmacological inhibition of DPP-4 enhanced T cell proliferation while also improving cytotoxic function of antigen-specific and CAR T cells. These changes were accompanied by upregulation of lymphocyte activation pathways, increased cellular respiration/glycolysis, and altered cellular metabolism, characterized by upregulation of tricarboxylic acid (TCA) cycle metabolites. The functional and metabolic reprogramming of CD8+ T cells were in part mediated by activation of glutamate decarboxylase (GAD), which feeds glutamate into the TCA cycle, and pharmacological inhibition of GAD mitigated sitagliptin-mediated T cell proliferation. Furthermore, GBM patients on DPP-4 inhibitors had better outcomes compared to those only receiving standard of care treatment. In summary, we show that pharmacological inhibition of DPP-4 promotes anti-tumorigenic function of CD8+ T-cell by prolonging effector function through metabolic reprograming. These findings support future translational efforts to repurpose DPP-4 inhibitors as immunotherapy agents for GBM and other cancers that are characterized by T cell dysfunction.