Dokument

Summary:
Pancreatic ductal adenocarcinoma carcinoma (PDAC) is one of the most lethal cancers in existence. In the last decades the survival of patients with PDAC did not improve. Therefore, it is vital to achieve a better understanding of how the disease influences and is influenced by the immune system. The tumor microenvironment (TME) of PDAC remodels the immune system to escape its immunosurveillance and to proliferate. Natural Killer cells (NK cells) contribute crucially in the recognition of cancer cells. The receptor NKG2D plays an important role in the activation of NK cells. By impairing the NKG2D axis, PDAC downregulates the NK cell activity and escapes from the immune response. Epigenetic modulators like histone deacetylase inhibitors (HDACi) have been shown to overcome this obstacle. In this context, the role of the oncoprotein SKI in cancer immunosurveillance is not known yet. In this work, the role of the oncoprotein SKI on the NK cell immunosurveillance and the benefit of HDACi treatment on PDAC cell lines was examined. Therefore, two PDAC cell lines were treated with the pan-HDACi LBH589. The LBH589 treatment led to an increase in cell death in PDAC cell lines. It was found as well that LBH589 treatment of PDAC results in an upregulation of the NKG2D ligands (NKG2D-L) MICA and ULBP2 and thus the NK cell conveyed killing was improved. The SKI protein level and NKG2D-L expression did not correlate with each other. Further examination of the role of SKI on NK cell immunosurveillance was performed by knockdown (KD) of SKI in PDAC by transfection with siRNA. The KD resulted into a strongly improved cancer cell killing suggesting that SKI acts as a major regulator in PDACs immune escape from NK cells. SKI does not solely mediate the immune escape through NKG2D-L suppression but rather by a not yet defined mechanism. Additionally, SKI suppresses the LBH589 mediated NKG2D-L upregulation and NK cell killing, indicating that SKI could act as a negative predictor for the outcome of HDACi treatment in PDAC. In conclusion, SKI acts as a major regulator of PDACs escape of NK cell conveyed immunosurveillance. The underlying mechanisms still need to be defined. The treatment of PDAC with HDACi seems to be promising and should be further investigated in in vivo studies. Additional NK cell-based immunotherapy or targeted therapies could further improve the patient´s outcome.

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