Untersuchung inflammatorischer Immunzellsubsets im Aszites von Ovarialkarzinom Patientinnen

Das Ovarialkarzinom entwickelt sich lange unbemerkt und wird meist erst in einem fortgeschrittenen Stadium diagnostiziert, in dem bereits Peritonealmetastasen und maligner Aszites auftreten. Welche Mechanismen dazu führen, dass in der Pathogenese zwar eine tumorassoziierte Inflammation, aber keine e...

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Bibliographic Details
Main Author: Schimanowski, Philipp Immanuel
Contributors: Wagner, Uwe (Prof. Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2015
Online Access:PDF Full Text
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Ovarian cancer is usually diagnosed at an advanced stage of disease often with peritoneal metastasis and malignant ascites. Tumor microenvironment and immunologic interactions are a key component of tumorigenesis. Different models suggest an immune escape mechanism, which prevents some tumors from cytotoxic effects by the host’s immune system. It is still not clear which mechanisms are responsible for prevention of an effective immune response. In particular, the exact immunologic function of TH17 cells during tumor progression remains largely unknown. To create further insight on these mechanisms, we studied the interactions of tumor-associated macrophages (TAM), TH17-cells, effector T-cells and regulatory T-cells (Treg) in ovarian cancer patients. Furthermore we evaluated their prognostic value for relapse free survival (RFS). The concentration of macrophages and the various T-cell-populations were investigated in ascites and peripheral blood of 20 patients suffering from high grade serous ovarian carcinoma. Various surface markers and cytokines (especially IL-17 and IFNg) were evaluated by Fluorescence Activated Cell Sorting (FACS). In functional assays the proliferative capacity of effector T-cells and the suppression by Tregs was quantified. Due to the poorer prognosis of patients with CD163low in ascetic fluid, a subgroup analysis of T cell subsets in patients with CD163low and CD163high TAMs was carried out. The results were tested for significant correlations by statistical analysis. Their impact on prognosis was studied by survival analysis. Supressive and promoting mechanisms should be revealed to enhance the understanding of the tumor development. Our findings suggest that TH17-cells are positively associated with the CD163 expression on TAMs in ascites. Consistent with these findings, the concentration of TH17-cells was reduced in ascites from CD163low patients compared to peripheral blood as well as the number of CD4+ T-helper cells. However, the proliferative capacity and IFNg expression of CD4+ T-helper cells in ascites was increased. The IFNg expression correlated positively to the frequency of TH17-cells, especially in the CD163low subset. In the CD163high subset in contrast IFNg expression was negatively associated to the CD163 and CD206 Expression on TAMs. In ascites Tregs suppressed significant effector T-cells but not TH17-cells. High concentrations of TH17-cells in ascites tend to correlate positively to RFS. Overall high levels of CD163 show an inverse correlation to RFS. One possible explanation could be the suppression of the effector-T-cell response by CD163 together with CD206. Our results show furthermore a positive association between CD163 and TH17-cells. However, TH17 cells seem to display an antitumor immune response by inducing the IFNg expression in effector-T-cells and to have a positive impact on RFS. Probably TH17-cells are not suitable as a solitary prognostic marker but in combination with other immunocytological subsets or soluble mediators in ascites. Possible correlations between the states of TAM polarization and the different T cell subpopulations should be tested in functional assays and could provide a basis for the development of new diagnostic and therapeutic options in ovarian cancer.