DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model

DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.3390/cancers13030487
Journal or Publication Title: Cancers
Volume: 13
Number: 3
Page Range: p. 487
Date: 2021
Divisions: Liver Enzymes in Metabolism and Inflammation
Depositing User: General Admin
Identification Number: 10.3390/cancers13030487
ISSN: 2072-6694
Date Deposited: 10 Jun 2021 06:06

Immunity plays a key role in epithelial ovarian cancer (EOC) progression with a well-documented correlation between patient survival and high intratumoral CD8+ to T regulatory cell (Treg) ratios. We previously identified dysregulated DPP4 activity in EOCs as a potentially immune-disruptive influence contributing to a reduction in CXCR3-mediated T-cell infiltration in solid tumours. We therefore hypothesized that inhibition of DPP4 activity by sitagliptin, an FDA-approved inhibitor, would improve T-cell infiltration and function in a syngeneic ID8 mouse model of EOC. Daily oral sitagliptin at 50 mg/kg was provided to mice with established primary EOCs. Sitagliptin treatment decreased metastatic tumour burden and significantly increased overall survival and was associated with significant changes to the immune landscape. Sitagliptin increased overall CXCR3-mediated CD8+ T-cell trafficking to the tumour and enhanced the activation and proliferation of CD8+ T-cells in tumour tissue and the peritoneal cavity. Substantial reductions in suppressive cytokines, including CCL2, CCL17, CCL22 and IL-10, were also noted and were associated with reduced CD4+ CD25+ Foxp3+ Treg recruitment in the tumour. Combination therapy with paclitaxel, however, typical of standard-of-care for patients in palliative care, abolished CXCR3-specific T-cell recruitment stimulated by sitagliptin. Our data suggest that sitagliptin may be suitable as an adjunct therapy for patients between chemotherapy cycles as a novel approach to enhance immunity, optimise T-cell-mediated function and improve overall survival.

Wilson, Amy L.
Moffitt, Laura R.
Wilson, Kirsty L.
Bilandzic, Maree
Wright, Mark D.
Gorrell, Mark D.
Oehler, Martin K.
Plebanski, Magdalena
Stephens, Andrew N.
Last Modified: 10 Jun 2021 06:06
URI: https://eprints.centenary.org.au/id/eprint/1033

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