Interaktion von Lymphomzellen und Makrophagen in einem in-ovo-Modell
Interaction of lymphoma cells and macrophages in an in-ovo model
by Anna Julia Leypoldt née Groenewold
Date of Examination:2024-11-21
Date of issue:2024-11-21
Advisor:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Jörg Wilting
Persistent Address:
http://dx.doi.org/10.53846/goediss-10829
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Abstract
English
In recent years, there has been increasing evidence that the tumor microenvironment plays a varying but important role in the development of lymphomas in different types of lymphoma and influences the success of treatment. Macrophages (Mφ) in the tumor microenvironment can promote tumor growth, which has already been clinically proven for Hodgkin's lymphoma in particular. However, the exact mechanisms and therapeutic options are still largely unclear. The structure of the microenvironment in Burkitt's lymphoma differs from that in diffuse large B-cell lymphoma (DLBCL), which in turn differs from that in Hodgkin's lymphoma. The aim of the present study was to utilize and further develop a preclinical xenograft model for the interaction between Hodgkin's lymphoma and Mφ that was recently developed in the research group. In this in ovo xenograft model of the interaction of lymphoma cells with Mφ, L-428 Hodgkin lymphoma cells, BL-2 Burkitt lymphoma cells and OCI-LY-3 and HBL-1 DLBCL lymphoma cells were comparatively analyzed. To investigate the influence of clinically relevant inhibitors, we chose ibrutinib as a prototype drug, which is already used clinically in chronic lymphocytic leukemia and in some diffuse large B-cell lymphomas. It is an inhibitor of Bruton's tyrosine kinase, which is not only important for B-cells but also plays a role in the function of cells of the innate immune system such as Mφ. Growth in ovo was demonstrated for the cell lines HBL-1 and OCI-LY-3, thus establishing a new xenograft model for DLBCL. The developed lymphomas differ in size and structure from L-428 and BL-2-in-ovo-lymphomas. Furthermore, it was shown that the investigated DLBCL-in-ovo-lymphomas grow larger in the presence of Mφ and migrate more clearly into the mesoderm. This indicates an increased invasiveness of the lymphoma cells by Mφ. Under the influence of ibrutinib, it was observed that the inhibitor primarily inhibited the viability of the DLBCL cell line HBL-1 and the Burkitt cell line BL-2 in vitro, while it led to an increase in viability in the Hodgkin cell line L-428. Ibrutinib had a consistently negative effect on the differentiation of monocytes into macrophages and inhibited the adhesion capacity of Mφ. In macrophages, the restriction of phosphorylation of AKT by ibrutinib was demonstrated. In the in-ovo-xenograft model, ibrutinib most likely had no effect on L-428 Mφ lymphomas. In HBL-1 Mφ-in-ovo-lymphomas, pretreatment with ibrutinib resulted in larger and more loosely structured tumors. Exemplarily, we were able to test the new method for examining in-ovo-lymphomas in small animal volume computed tomography, which may provide important insights into the structure of tumors in the future. In summary, this work provides several in-ovo-models for the analysis of the interaction of lymphoma cells with Mφ, allowing not only to study the mechanisms of cell-cell interactions in the tumor microenvironment, but also to test the effect of lymphoma drugs on these interactions in a preclinical model.
Keywords: Lymphoma; Macrophages; tumor microenvironment; Ibrutinib; DLBCL; Hodgkin's lymphoma; Burkitt's lymphoma; xenograft model
