Abstract
Exhaustion of CD8+ T cells in the tumor microenvironment is intertwined with metabolic dysfunction. Thus, metabolic reinvigoration of T cells is a promising cancer immunotherapy strategy. Here, we identify dipeptidyl peptidase 4 (DPP-4) as an immune checkpoint molecule driving the hypometabolic state of exhausted CD8+ T cells. We found that DPP-4 is highly expressed by CD8+ T cells infiltrating brain tumors, and its expression levels increase with terminal exhaustion. Pharmacological inhibition of DPP-4 with the FDA-approved sitagliptin, which is used for the management of type II diabetes, transcriptionally and metabolically reprogrammed CD8+ T cells to upregulate lymphocyte activation pathways and enhance mitochondrial spare respiratory capacity. Functionally, DPP-4 inhibition increased proliferation, antigen-specific cancer cell killing capability, and cytotoxic mediator production of mouse CD8+ T cells and IL13Ra2 CAR T cells in vitro. Mechanistically, inhibiting DPP-4 upregulated glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle. Pharmacological inhibition of GAD1 abrogated sitagliptin-mediated T cell proliferation and metabolic reprograming of mouse and human CD8+ T cells, underscoring a new role for this enzyme in T cell functional regulation. Systemic inhibition of DPP-4 prolonged survival in preclinical glioblastoma (GBM) models in a CD8+ T cell-dependent manner. Furthermore, retrospective analysis indicated that GBM patients on DPP-4 inhibitors, gliptins, have better outcomes compared to those receive standard of care alone or in combination with metformin. Collectively, our results support repurposing the clinically used and well-tolerated class of DPP-4 inhibitors to enhance cancer immunotherapy responses.