Exploring molecular patterns and determinants of melanoma cell susceptibility to natural killer cell cytotoxicity

by Sabrina Cappello
Doctoral thesis
Date of Examination:2020-06-16
Date of issue:2020-07-16
Advisor:Dr. Ivan Prof Bogeski
Referee:Prof. Dr. Alexander Flügel
Referee:Prof. Dr. Michael P. Schön
Persistent Address: https://dx.doi.org/10.53846/goediss-8083

 

 

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Abstract

English

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.
Keywords: Melanoma; Natural killer cells; Immunotherapy; SNAI1; DIABLO; PI3K-AKT-mTOR pathway; NK cell resistance
 
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