Sitagliptin alters metastatic progression and immune response in an ID8 ovarian cancer mouse model

Wilson AL1,2, Wilson KL2, Moffitt LR1,2, Bilandzic M1,2, Plebanski M2,3 and Stephens AN1,2

  1. Hudson Institute of Medical Research, VIC, Australia.
  2. Monash University, VIC, Australia.
  3. RMIT University, VIC, Australia.

Current methods used to treat epithelial ovarian cancer (EOC) often result in relapse and acquired chemo-resistance; therefore, novel therapies for EOC are urgently needed. Immunotherapy for EOC is gaining traction, and recent studies have suggested that the dipeptidyl peptidase-4 (DPP4) inhibitor sitagliptin can activate the immune system, but this has not been demonstrated in ovarian cancer. Additionally, preclinical models that accurately stage ovarian tumour growth are required for evaluating these therapeutic responses in vivo, as no non-invasive techniques currently exist. We developed a model in which ID8 mouse ovarian cancer cells stably express a near-infrared protein (iRFP) via integration into the ROSA26 genomic region, then used this model to evaluate the anti-tumour effects of sitagliptin in vivo. C57BL/6 mice received an injection of 1x106 pROSA-iRFP720-ID8 EOC cells under the ovarian bursa. Mice were treated with sitagliptin (50mg/kg/body-weight/day) 14-days following implantation until endpoint, and iRFP720 fluorescence was measured weekly to evaluate tumour deposition. T-cell, dendritic cell (DC), macrophage and myeloid-derived suppressor cell (MDSC) populations in the spleen, lymph nodes and blood were assessed by flow cytometry, and in tumour tissue by immunofluorescence. We demonstrated that administration of sitagliptin reduced tumour burden, as indicated by fluorescence and macroscopic tumour observations. Sitagliptin increased tumour-infiltrating T-effector cells, decreased proliferating T-regulatory cells and decreased cytotoxic T-cell apoptosis. In addition, sitagliptin increased circulating DCs and macrophages, and decreased tumour-associated MDSCs. Taken together, these results suggest that administration of sitagliptin decreases tumour burden in an ID8 ovarian cancer model by shifting the balance toward anti-tumour immunity, and it may have therapeutic potential for epithelial ovarian cancer.