Hodgkin lymphoma secreted factors determine macrophage polarization and function

by Annekatrin Arlt
Doctoral thesis
Date of Examination:2018-09-06
Date of issue:2018-09-14
Advisor:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Jörg Wilting
Persistent Address: http://dx.doi.org/10.53846/goediss-7054

 

 

Files in this item

Name:PhDthesis_AArlt.pdf
Size:3.02Mb
Format:PDF

The following license files are associated with this item:

Abstract

English

Hodgkin lymphoma (HL) is a unique entity where the fraction of malignant cells accounts for only 1 % of the tumor. The cells are embedded in a complex background of non-neoplastic immune infiltrates. Profound interactions of the malignant cells with neighboring cells are a requisite to sustain their survival and allow tumor development. Among the cell types commonly found in the HL tumor mass are macrophages whose presence has been associated with poor prognosis. Macrophages are innate immune cells and critical regulators of immune responses and tissue remodeling. They are known to occur in all cancer types where they exhibit various functions to promote tumor growth and metastasis. This study aims to gain a deeper insight into the interplay of HL cells with macrophages. Herein, we show that HL cells actively recruit macrophages. Using Boyden chamber assays we found that monocytes and macrophages migrate toward HL conditioned medium (CM). Applying CM directly on the cells further revealed that factors in the CM support the differentiation of monocytes into macrophages and macrophage repolarization. By the analyses of selected markers via flow cytometry and qRT PCR we found that these macrophages expose an M2 like phenotype. A characteristic feature was their high CD206 expression. Investigations into the functional consequence of high CD206 expression included endocytosis assays and revealed an enhanced uptake of CD206 specific targets. Alongside we found that macrophages secret high amounts of MMP-9 and alter the tumor formation of HL cells in a chorion allantois membrane assay. By applying selected factors on monocytes we found that the increased CD206 expression in HL derived macrophages could be a result of IL-13 produced by HL cells. Further analysis of the phenotype of HL derived macrophages included RNA sequencing and revealed an enrichment of upregulated genes involved in antigen presentation and as well co stimulation and inhibition. Taken together, these findings support a model in which HL cells secret factors to attract and generate macrophage with a specific M2-like activation state. Analyses of their phenotype and features indicate that these cells serve functions in tissue remodeling and T cell interaction.
Keywords: Hodgkin lymphoma; macrophages
 
Statistik