Abstract
Simple SummaryPancreatic ductal adeno carcinoma is one of the most lethal solid tumors and the survival rate has not improved significantly over the past decades. The disease is characterized by an immune-suppressive tumor microenvironment, which promotes the limited response to novel immunotherapies. The aim of our study was to contribute to a better understanding of the diminished Natural Killer (NK) cell-activity in pancreatic cancer. We showed that oncoprotein SKI, which is involved in CBP/p300-mediated acetylation, diminished the expression of activating ligands for the cytotoxicity receptor NKG2D on tumor cells, thereby counteracting NK cell-dependent cytotoxicity. Treatment of tumor cells with histone deacetylase inhibitors (HDACi) induced the expression of these ligands and improved NK cell-dependent killing. Thus, we unraveled a so far unknown role of SKI in NK cell-mediated immunosurveillance. Our results suggest that the combination of HDACi with NK cell-based immunotherapies may be beneficial for pancreatic cancer patients.Drugs targeting epigenetic mechanisms such as histone deacetylase inhibitors (HDACi) suppress tumor growth. HDACi also induce the expression of ligands for the cytotoxicity receptor NKG2D rendering tumors more susceptible to natural killer (NK) cell-dependent killing. The major acetylases responsible for the expression of NKG2D ligands (NKG2D-L) are CBP and p300. The role of the oncogene and transcriptional repressor SKI, an essential part of an HDAC-recruiting co-repressor complex, which competes with CBP/p300 for binding to SMAD3 in TGFβ signaling, is unknown. Here we show that the siRNA-mediated downregulation of SKI in the pancreatic cancer cell lines Panc-1 and Patu8988t leads to an increased target cell killing by primary NK cells. However, the higher cytotoxicity of NK cells did not correlate with the induction of NKG2D-L. Of note, the expression of NKG2D-L and consequently NK cell-dependent killing could be induced upon LBH589 (LBH, panobinostat) or valproic acid (VPA) treatment irrespective of the SKI expression level but was significantly higher in pancreatic cancer cells upon genetic ablation of SKI. These data suggest that SKI represses the inducible expression of NKG2D-L. The combination of HDACi with NK cell-based immunotherapy is an attractive treatment option for pancreatic tumors, specifically for patients with high SKI protein levels.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) represents 85% of all pancreatic cancers and exhibits the poorest prognosis of all solid tumors
PDAC is characterized by an immune-suppressive tumor microenvironment (TME) producing TGFβ and other factors to counteract immunosurveillance, while promoting tumor growth and metastasis for example, through the recruitment of tumor supporting macrophages [5]
Data for pancreatic cancer cells are rare, the upregulation of MICA/B upon treatment of tumor cell lines with valproic acid (VPA) through the induction of the PI3K/AKT signaling pathway was described [22]
Summary
Pancreatic ductal adenocarcinoma (PDAC) represents 85% of all pancreatic cancers and exhibits the poorest prognosis of all solid tumors. Incidence rates in the industrialized world are steadily increasing and the 5-year survival rate is below 10% with a median survival of 6 months [1,2,3]. Reasons for the poor prognosis include delayed diagnosis associated with non-resectable locally advanced or metastatic disease and chemo-resistance. One component which critically contributes to drug resistance is the peritumoral desmoplasia, which impairs intra-tumoral drug delivery [4]. PDAC is characterized by an immune-suppressive tumor microenvironment (TME) producing TGFβ and other factors to counteract immunosurveillance, while promoting tumor growth and metastasis for example, through the recruitment of tumor supporting macrophages [5].
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