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Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer

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Abstract

Pancreatic ductal adenocarcinoma is a leading cause of cancer mortality with a dismal 2–5 % 5-year survival rate. Monotherapy with Gemcitabine has limited success, highlighting the need for additional therapies that enhance the efficacy of current treatments. We evaluated the combination of Gemcitabine and Rosiglitazone, an FDA-approved drug for the treatment of type II diabetes, in an immunocompetent transplantable mouse model of pancreatic cancer. Tumor progression, survival, and metastases were evaluated in immunocompetent mice with subcutaneous or orthotopic pancreatic tumors treated with Pioglitazone, Rosiglitazone, Gemcitabine, or combinations of these. We characterized the impact of high-dose Rosiglitazone and Gemcitabine therapy on immune suppressive mediators, including MDSC and T regulatory cells, and on modulation of peripheral and intra-tumoral T cell populations. Combinations of Rosiglitazone and Gemcitabine significantly reduced tumor progression and metastases, enhanced apoptosis, and significantly extended overall survival compared to Gemcitabine alone. Rosiglitazone altered tumor-associated immune suppressive mediators by limiting early MDSC accumulation and intra-tumoral T regulatory cells. Combination therapy with Rosiglitazone and Gemcitabine modulated T cell populations by enhancing circulating CD8+ T cells and intra-tumoral CD4+ and CD8+ T cells while limiting T regulatory cells. The results suggest that Rosiglitazone, in combination with Gemcitabine, decreases immune suppressive mechanisms in immunocompetent animals and provides pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic cancer.

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Acknowledgments

The authors thank the UNMC Comparative Medicine for their excellent care of our mice, the UNMC Histology Facility, and the UNMC Monoclonal Antibody facility. We also would like to thank Dr. Jane Meza for her help with our statistical analyses. This work was supported by grants from the National Institutes of Health (R03 CA149857, R01CA57362, U01CA111294, P50 CA127297), NCI training grant (CA09476) and student assistantship awards from the University of Nebraska and NCI Cancer Center Grant P30CA36727.

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The authors have no conflict of interest.

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  1. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE, 68198, USA

    Stephanie K. Bunt, Ashley M. Mohr, Jennifer M. Bailey, Paul M. Grandgenett & Michael A. Hollingsworth

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  1. Stephanie K. Bunt
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  2. Ashley M. Mohr
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Correspondence to Michael A. Hollingsworth.

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Bunt, S.K., Mohr, A.M., Bailey, J.M. et al. Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer. Cancer Immunol Immunother 62, 225–236 (2013). https://doi.org/10.1007/s00262-012-1324-3

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