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dc.contributor.advisor Bogeski, Ivan Prof Dr.
dc.contributor.author Cappello, Sabrina
dc.date.accessioned 2020-07-16T07:20:41Z
dc.date.available 2021-06-14T00:50:12Z
dc.date.issued 2020-07-16
dc.identifier.uri http://hdl.handle.net/21.11130/00-1735-0000-0005-1420-0
dc.language.iso eng de
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 610
dc.title Exploring molecular patterns and determinants of melanoma cell susceptibility to natural killer cell cytotoxicity de
dc.type doctoralThesis de
dc.contributor.referee Flügel, Alexander Prof. Dr.
dc.date.examination 2020-06-16
dc.description.abstracteng Malignant melanoma is the deadliest form of skin cancer. Due to its genetic heterogeneity and high potential to metastasize, the treatment of melanoma is challenging. Despite the promising result of T-cell based therapeutic strategies in combination with targeted therapies, therapeutic resistance or relapse occur. Hence, the advancement and improvement of melanoma immunotherapies need to be considered. Natural killer (NK) cells, which show an innate ability to recognize and kill cancer cells without prior sensitization, could be a useful additional therapeutic tool in melanoma immunotherapy. To investigate the therapeutic potential of NK cells, we assessed the cytotoxicity of primary NK cells as well as the NK-92 cell line to genetically diverse human melanoma cell lines. A broad range of susceptibility of different melanomas to activated NK cells was observed. Proteome analyses (RPPA) of melanoma cells indicated a correlation between melanoma protein expression and susceptibility to NK cells and allowed the establishment of a ‘melanoma killing signature’. Using this novel tool the NK cell-mediated killing of additional and untested melanoma cell lines was successfully predicted. Furthermore, manipulation of single identified proteins such as SNAI1 and signalling pathways such as the PI3K-AKT-mTOR pathway affected the NK cell-mediated killing of melanoma cells. The success of immune therapy is not only dependent on the initial positive treatment effect but also the prevention of therapy resistance. Therefore, melanoma-NK cell co-cultures in order to identify new molecular targets, which might control NK cell escape mechanisms in melanoma, were established. NK cell resistance in melanoma cells seems to be strongly associated with the downregulation of MHC class I but also MHC class II molecules. In summary, this study identifies novel prognostic immunotherapy-response biomarkers and possible resistance mechanism and thus reveals new insights into the potential use of NK cells in melanoma therapy. de
dc.contributor.coReferee Schön, Michael P. Prof. Dr.
dc.subject.eng Melanoma de
dc.subject.eng Natural killer cells de
dc.subject.eng Immunotherapy de
dc.subject.eng SNAI1 de
dc.subject.eng DIABLO de
dc.subject.eng PI3K-AKT-mTOR pathway de
dc.subject.eng NK cell resistance de
dc.identifier.urn urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-1420-0-0
dc.affiliation.institute Medizinische Fakultät
dc.subject.gokfull GOK-MEDIZIN de
dc.subject.gokfull Biologie (PPN619875151) de
dc.description.embargoed 2021-06-14
dc.identifier.ppn 1725042223

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