Teran Pumar, O. Y.; VanNoy, E. L.; Haffey, A.; Gannamedi, D. P.; Rafie, C. I.; Lykke Harwood, D. S.; Benedetti, J. R.; Pittman Ballard, C. A.; Ciervo, E.; Assenza Tavares Coroa, P. H.; Grover, P.; Leon, B. E.; Mitchell, J.; Pathak, A.; Colon, B.; El Ghorayeb, L.; O'Sullivan, L.; Venkatarame Gowda Saralamma, V.; Lopez Ruiz, C.; Khatwani, N.; Surinder, K.; Rai, P.; Schatz, J.; Shah, A.; Binder, Z.; Ceccarelli, M.; Ostrom, Q. T.; Kristensen, B. W.; Stelekati, E.; Watson, D. C.; Lombard, D. B.; Haydar, D.; Bayik, D.

Metabolic dysfunction is a hallmark of CD8+ T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8+ T cells via metabolic reprogramming. Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8+ T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8+ T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8+ T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability. The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8+ T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8+ T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors. Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM. Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8+ T cell responses.