Universität zu Köln

Steinmetz, Greta (2023). Regulation of PD-L1 surface expression on CLL cells by small molecule inhibitors and the functional consequences on T cell mediated cytotoxicity. PhD thesis, Universität zu Köln.

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Abstract

PD-L1 and its receptor PD-1 are surface proteins on many different cells that are involved in the immune response in the human body. Binding of the ligands to its receptor inhibits the immune response, which physiologically prevents an exuberant immune response at the so-called immune checkpoints. However, PD-L1 is also expressed on tumor cells, for example on CLL cells, and thus leukemic cells can counter tumor immune evasion. The PD-L1/ PD-1 axis is used as a therapeutic target in oncology to enhance the immune defense against tumor cells. For this purpose, the so-called checkpoint inhibitors are used, which block the interaction between the ligand and the receptor. In this work, we focused on the regulation of PD-L1 expression on primary CLL cells. On the one hand, PD-L1 expression on the cell surface can be stimulated by different methods, and on the other hand, a reduction of PD-L1 on primary CLL cells is achieved by different checkpoint inhibitors. We particularly focused on the inhibitor dasatinib, as it showed the clearest effect in reducing PD-L1 expression. In different experiments, we tested the role of the B-cell receptor signaling pathway and influence of its individual kinases on the regulation of PD-L1 expression. In these experiments, the B-cell receptor signaling pathway was not shown to be a critical regulator. Since dasatinib is toxic to cells and is known to cause many clinical side effects, it were strictly considered only viable CLL cells in the experiments to exclude the impressive reduction of PD-L1 on CLL cells by a toxic effect alone. A significant reduction of PD-L1 could also be achieved on high risk CLL cells by dasatinib treatment. This points out dasatinib as a potential therapy for high risk CLL patients. Further, the effect of PD-L1 expressing CLL cells on T cells was investigated. For this purpose, different conditions of B-T cell co-cultures with high or low PD-L1 expression on CLL cells and activated or inactivated T cells were applied. Initial results confirmed the hypothesis that CLL cell survival is more markedly reduced by activated T cells and that the T cell response is inhibited by highly expressed PD-L1. However, these results need further validation. Our idea is to visualize the interaction between B and T cells by live imaging. A future goal is to establish dasatinib plus a PD-L1 antibody as a combination therapy for CLL. This could expand the therapeutic options for high-risk CLL patients who respond to immunotherapy.

Item Type:	Thesis (PhD thesis)
Translated title:	Title Language UNSPECIFIED English
Creators:	Creators Email ORCID ORCID Put Code Steinmetz, Greta greta.steinmetz@uk-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-705591
Date:	28 July 2023
Language:	English
Faculty:	Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language CLL, PD1, PD-L1 English
Date of oral exam:	12 June 2023
Referee:	Name Academic Title Hallek, Michael Universitätsprofessor Dr. med.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/70559