TY  - THES
T1  - B7-H1 as a new molecular target for the treatment of pancreatic adenocarcinoma
T3  - Giessen : Laufersweiler
A1  - Ahn,Katharina
Y1  - 2015/09/03
N2  - PDAC remains today a devastating disease characterized by a poor prognosis and low survival rates in patients. This is primarily due to its late recognition, high metastasis rates and poor response to curative therapies such as chemotherapy or radiation. Immune therapy could provide promising opportunities for the treatment of PDAC. But first, it is important to analyze the immune system of PDAC patients, respectively mice. In this work, we analyzed the precise role of the B7-H1 expression on cells of the immune system, with the main focus on MDSC in the context of anti-tumor immunity in PDAC in both in vitro and in vivo experiments using WT and B7-H1 KO healthy and tumor-bearing mice. Higher ratios of CD4+ /CD8+ Tem and Tcm were seen in splenocytes of B7-H1 KO compared to WT healthy and tumor-bearing mice. The analysis of the MDSC population revealed lower frequencies of total MDSC in spleens of B7-H1 KO compared to spleens of WT tumor-bearing mice. After the 5-FU and IFNalpha+5-FU treatment, higher ratios of MDSC were seen in B7-H1 KO spleens. In tumors of B7-H1 KO mice, significantly lower ratios of MDSC and a decreased ratio of gMDSC were observed compared to that in WT tumor-bearing mice. Furthermore, significantly lower ratios of iNOS+ gMDSC and mMDSC were determined in tumors of B7-H1 KO compared to untreated WT tumor-bearing mice. In splenocytes of tumor-bearing WT mice, a significant decrease in B7-H1 MFI of total MDSC was found after treatment with IFNalpha+5-FU. Lower VEGF concentrations were found in serum samples of B7-H1 KO compared to WT tumor-bearing mice, and higher concentrations were found in medium supernatants in the presence of WT MDSC. The analysis of IL-1ß revealed significantly lower concentrations in serum samples of B7-H1 KO compared to WT tumor-bearing mice. For IFNɣ, significantly higher concentrations were found in medium supernatants containing B7-H1 KO splenocytes. In our survival experiment series, we demonstrated a significantly higher survival rate as well as a lower tumor frequency, tumor volume and distant metastasis rate in B7-H1 KO compared to WT mice, regardless the chosen treatment. Beyond that, a significantly lower tumor volume was determined after treatment of both mouse strains with 5-FU and IFNalpha+5-FU. In summary, through this work we characterized the immune system of WT and B7-H1 KO healthy and PDAC -bearing mice with a main focus on the molecule B7-H1 and MDSC, as well as the impact of chemo- and immune therapy.
CY  - Gießen
PB  - Universitätsbibliothek
SN  - 978-3-8359-6352-8
AD  - Otto-Behaghel-Str. 8, 35394 Gießen
UR  - http://geb.uni-giessen.de/geb/volltexte/2015/11672
ER  -