Pharmacologic DPP-4 inhibition promotes CD8 T cell metabolic fitness to enhance anti-tumor activity

Authors

• Oriana Y. Teran Pumar, Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Elton L. VanNoy, George Washington University, School of Medicine and Health Sciences, USA.
• Abigail Haffey, George Washington University, School of Medicine and Health Sciences, USA.
• Durga Prasad Gannamedi, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Christine Isabelle Rafie, Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Dylan Scott Harwood, The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
• Julia R. Benedetti, Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
• Christine Ann Ballard, Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
• Erika Ciervo, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Pedro Henrique Coroa, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Payal Grover, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
• Brandon Emanuel León, Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Jonathan Mitchell, Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Asmita Pathak, Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Bruno Colon, Department of Molecular & Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Lyenne El Ghorayeb, Children's National Research Institute, USA.
• Laura O'Sullivan, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
• Venu Venkatarame Saralamma, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Clara Lopez Ruiz, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Natasha Khatwani, Department of Pathology and Laboratory Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
• Surinder Kumar, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Priyamvada Rai, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Jonathan Schatz, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Ashish Shah, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Zev A. Binder, Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
• Michele Ceccarelli, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Quinn T. Ostrom, Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
• Bjarne Winther Kristensen, The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
• Erietta Stelekati, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Dionysios C. Watson, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• David B. Lombard, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
• Dalia Haydar, George Washington University, School of Medicine and Health Sciences, USA.

Document Type

Journal Article

Publication Date

4-3-2026

Journal

bioRxiv : the preprint server for biology

DOI

10.64898/2026.03.31.715681

Abstract

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.

APA Citation

Teran Pumar, Oriana Y.; VanNoy, Elton L.; Haffey, Abigail; Gannamedi, Durga Prasad; Rafie, Christine Isabelle; Harwood, Dylan Scott; Benedetti, Julia R.; Ballard, Christine Ann; Ciervo, Erika; Coroa, Pedro Henrique; Grover, Payal; León, Brandon Emanuel; Mitchell, Jonathan; Pathak, Asmita; Colon, Bruno; Ghorayeb, Lyenne El; O'Sullivan, Laura; Saralamma, Venu Venkatarame; Ruiz, Clara Lopez; Khatwani, Natasha; Kumar, Surinder; Rai, Priyamvada; Schatz, Jonathan; Shah, Ashish; Binder, Zev A.; Ceccarelli, Michele; Ostrom, Quinn T.; Kristensen, Bjarne Winther; Stelekati, Erietta; Watson, Dionysios C.; Lombard, David B.; and Haydar, Dalia, "Pharmacologic DPP-4 inhibition promotes CD8 T cell metabolic fitness to enhance anti-tumor activity" (2026). GW Authored Works. Paper 9120.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/9120

Department

Pediatrics