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The influence of secretogranin 2 on the assembly and presentation of the MHC class I complex in melanoma
Melanoma is the reason for the majority of skin cancer-related deaths and reports a rising incidence over the past years. It arises from transformed melanocytes, the melanin-producing skin cells. The primary cause of melanoma is high exposure to ultra violet (UV) radiation. Besides UV radiation, also other factors like genetic predisposition or a weakened immune system can contribute to melanoma development. Depending on the cancer stage, location, and genetic profile different treatment options exist. Gaining new insights into the underlying mechanisms of melanoma progression contributed to the development of new treatment options, such as targeted therapies or immunotherapies. Unfortunately, the development of resistances against treatments negatively influences the therapy success. Therefore, therapy success could be improved through better understanding of the mechanisms leading to therapy resistance and developing potent new therapeutic approaches. Previous work in our laboratory on the histone methyltransferase SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) revealed a possible role of secretogranin II (SCG2) in melanoma pathogenesis. The results showed that high intratumoral SCG2 expression in melanoma patients correlates with poor survival rates. Based on these data, there was reason to further examine the role of SCG2 in melanoma. The aim of this project was to investigate the role of SCG2 in melanoma through identifying mechanisms that are influenced by SCG2. First, I could demonstrate that primary melanoma and melanoma metastases show high SCG2 expression levels. By comparing the gene expression levels between SCG2-overexpressing (OE) and control melanoma cells, I found a downregulation of components of the antigen presenting machinery (APM). The components of the APM are important for the correct assembly of the MHC class I complex. Using flow cytometry analysis, I could show that the surface MHC class I levels were downregulated in SCG2 OE melanoma cells. Due to the downregulation of MHC class I, these cells were less sensitive towards cytotoxic T cell-induced killing. The consequences of SCG2 OE on the expression of several APM components, MHC class I surface presentation, and sensitivity towards cytotoxic T cells could be partially reversed by IFNγ treatment. Taken together, these findings could contribute to the understanding of melanoma immune evasion mechanisms and the role of SCG2 in this process. Consequently, when it comes to the success of checkpoint blockade and adoptive immunotherapy, SCG2 could be a valuable prognostic factor. Also, new insights into the pathways involved in SCG2-induced MHC class I downregulation could open up new possibilities for melanoma treatment.
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570 Biowissenschaften, Biologie
570 Life sciences