| 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.identifier.uri | https://dx.doi.org/10.53846/goediss-8083 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-8083 | |
| 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 | |