Universität zu Köln

Heimsoeth, Alena (2024). Natural killer cell mediated killing of patient-derived lung cancer models in co-culture: An approach to unravel killing mechanisms. PhD thesis, Universität zu Köln.

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Abstract

Lung cancer is the most common malignancy and the leading cause of cancer mortality worldwide and the limited understanding of the complex interplay between the immune system and tumor cells hampers the development of novel therapies (Sung, 2021). Natural killer (NK) cells are lymphocytes and are highly cytotoxic against transformed cells without prior sensitization and thus play an important role in the development of lung cancer and other tumor types. It was shown that a NK cell gene signature within the tumor leads to a better overall survival (Habif, Crinier, Andre, Vivier, & Narni-Mancinelli, 2019; Larsen, Gao, & Basse, 2014; Takanami, Takeuchi, & Giga, 2001). The importance of NK cells in anti-tumor immunity is indisputable, but during tumor progression cancer cells escape their cytolytic function with various mechanisms (Sordo-Bahamonde, Lorenzo-Herrero, Payer, Gonzalez, & Lopez-Soto, 2020). This work aims to unravel dynamics between NK cells and lung cancer cells, investigating the prospects of cancer cell vulnerability, mechanisms of cell death and dynamics within short- and long-term co-culture. In this work I established a co-culture system of the human NK cell line NK-92 and patient-derived lung cancer cell lines in 2D and 3D to measure and mechanistically dissect NK cell killing efficacy. NK-92 were able to induced cell death in the majority of cell lines with a heterogenous pattern of killing efficacy between the individual lung cancer cell lines. Key findings of this work were; firstly, the identification of an epithelial-to-mesenchymal phenotype (EMT) gene signature in NK resistant cancer cell lines also reflected in a reduced killing of TGF treated cell lines; secondly, increased IFN signaling for highly sensitive cell lines; and thirdly, elevated cell death levels and less effect of caspase inhibition in highly vulnerable cancer cells.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Heimsoeth, Alena UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-731102
Date:	2024
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Sonstiges > Translationale Genomik
Subjects:	Natural sciences and mathematics Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Lung Cancer UNSPECIFIED NK cells UNSPECIFIED
Date of oral exam:	24 May 2024
Referee:	Name Academic Title Sos, Martin L Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/73110