The effects of Cancer Associated Fibroblasts on mechanisms of immune evasion in a rat chemical mammary carcinoma model
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1
Hacettepe University Cancer Institute, Basic Oncology, Türkiye
Objective: Fibroblast cells turn into cancer associated fibroblasts(CAFs) in tumor microenvironment. Tissue fibroblasts have previously been shown to affect T-cell functions. However, studies investigating the effects of CAFs on T-cells are limited in the literature.
Methods: N‐Nitroso N‐Methyl Urea(NMU) induced experimental mammary carcinogenesis model was utilized. Tumors were harvested surgically under sterile conditions for CAF isolation. CAFs and healthy tissue fibroblasts were immunostained to evaluate expression differences of markers like α‐Smooth-Muscle-Actin(αSMA) and Vimentin. DNA damage of peripheral blood cells due to NMU were analyzed by Comet Assays. Cocultures of CAFs with lymphocytes employing Carboxyfluoresceinsuccinimidyl-ester(CFSE) proliferation assays were performed. Surface and intracellular expressions of immune activation markers (CD25, IFN-γ) of T-cells cocultured with CAFs were analyzed. Levels of IL-4 were analyzed in CAF-splenocyte cocultures. Gene expression levels of several immune activation markers like CD25 and costimulatory molecules like CD28 in splenocytes were investigated.
Results: The immunostainings showed that CAFs had significantly higher levels of αSMA expression. Comet Assays showed that levels of DNA damage in tumor-bearing animals were similar to control levels. CAFs decreased proliferations of splenocytes in cocultures. Flow cytometry experiments showed that CAFs decreased intracellular expressions of immune activation markers like IFN-γ in T-cells. Supernatants of CAFsplenocyte cocultures were shown to have increased levels of IL-4. Splenocytes cocultured with CAFs were found to have decreased gene expression levels of costimulatory molecules.
Conclusions: A rat chemical breast carcinogenesis model was successfully employed and CAFs were stably propagated. Coculture experiments suggested an immunomodulatory role for CAFs on immunity against breast cancer.
Acknowledgements
This project was financially supported by The Scientific and Technological Research Council of Turkey.
References
1. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170(6):1807-16.
2. Filer A, Parsonage G, Smith E, Osborne C, Thomas AM, Curnow SJ, et al. Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils. Arthritis Rheum. 2006;54(7):2096-108.
Keywords:
chemical carcinogenesis,
fibroblast,
Mammary Carcinoma,
microenvironment,
tumor immunology
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune-mediated disease pathogenesis
Citation:
Gunaydin
G,
Dolen
Y,
Unver
N,
Kesikli
S and
Guc
D
(2013). The effects of Cancer Associated Fibroblasts on mechanisms of immune evasion in a rat chemical mammary carcinoma model.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.01132
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Received:
18 Jul 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Gurcan Gunaydin, Hacettepe University Cancer Institute, Basic Oncology, Ankara, 06100, Türkiye, gurcangunaydin@hacettepe.edu.tr