The Next Notch: Mesenchymal Stem Cells The Next Notch: Mesenchymal Stem Cells and their influence on the Hodgkin Lymphoma Microenvironment

Kahle, X.U. (Xaver) (2014) The Next Notch: Mesenchymal Stem Cells The Next Notch: Mesenchymal Stem Cells and their influence on the Hodgkin Lymphoma Microenvironment. thesis, Medicine.

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Abstract

It is believed that within the heterogeneous tumor microenvironment of Hodgkin Lymphoma (HL) the extensive cellular infiltrate might create an immunosuppressive milieu enabling malignant Hodgkin and Reed Sternberg (HRS) cells to evade an effective immune response. It has been postulated that among the majority of T cells residing within the tumor stroma of HL, regulatory T cells (Tregs) might play a key role in suppressing an adequate anticancer response. Furthermore, mesenchymal stem cells (MSCs), also found among the cells infiltrating HL-affected lymph nodes, have been suggested to positively influence differentiation of CD4+, naive T cells towards Tregs. We hypothesized that HRS cells might somehow activate MSCs within the microenvironment, in order to use them as relay workers to recruit Tregs via a Notch-signaling-mediated mechanism. To test this hypothesis we initially measured basal expression of Notch-1 and Jagged-1 in HL cell lines and primary MSCs. Furthermore we treated MSCs with medium from HL cell lines and observed the effect on Jagged-1 expression by means of flow cytometry analysis. Moreover we used these cells to induce Tregs from a population of CD4+ T cells and evaluated the effect of MSCconditioned medium on T cells. The results from experiments using conditioned media of cHL cell lines to treat MSCs suggest a considerable soluble factor-mediated upregulation of the Notch-ligand Jagged-1, supporting our hypothetical concept of HL-mediated MSC activation. Furthermore MSCs that had been incubated HL supernatants, recruited a far greater proportion of Tregs from a CD4+ T cell population than on baseline. A process that we might be mediated by paracrine Notch-signaling. We can conclude that soluble factors in HL-conditioned medium might be able to upregulate Jagged-1 expression in MSCs, enabling them to recruit Tregs from a population of CD4+ T cells. In addition MSCs might be able and attract T cells to the microenvironment.

Item Type:	Thesis (Thesis)
Supervisor name:	Kallenberg, Prof. Cees and Visser, Lydia
Supervisor name:	Aldinucci, Dr. Donatella and Celegato, Marta and National Cancer Institute and Italy
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:48
Last Modified:	25 Jun 2020 10:48
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/948

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