Journal article
Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer
Cancer immunology, immunotherapy : CII, Vol.62(2), pp.225-236
08/05/2012
DOI: 10.1007/s00262-012-1324-3
PMCID: PMC3873637
PMID: 22864396
Abstract
Pancreatic ductal adenocarcinoma (PDA) 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 Gemcitable modulated T cell populations by enhancing circulating CD8
+
T cells and intra-tumoral D4
+
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 provide pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic cancer.
Details
- Title: Subtitle
- Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer
- Creators
- Stephanie K. Bunt - University of Nebraska Medical CenterAshley M. Mohr - University of Nebraska Medical CenterJennifer M. Bailey - University of Nebraska Medical CenterPaul M. Grandgenett - University of Nebraska Medical CenterMichael A. Hollingsworth - University of Nebraska Medical Center
- Resource Type
- Journal article
- Publication Details
- Cancer immunology, immunotherapy : CII, Vol.62(2), pp.225-236
- DOI
- 10.1007/s00262-012-1324-3
- PMID
- 22864396
- PMCID
- PMC3873637
- ISSN
- 0340-7004
- eISSN
- 1432-0851
- Grant note
- P50 CA127297 || CA / National Cancer Institute : NCI R03 CA149857 || CA / National Cancer Institute : NCI P30 CA036727 || CA / National Cancer Institute : NCI
- Language
- English
- Date published
- 08/05/2012
- Academic Unit
- Family and Community Medicine
- Record Identifier
- 9984297334402771
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