The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC

Abstract

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.

The Immune Microenvironment in Pancreatic Cancer

“…Independently, it was demonstrated that gemcitabine may also trigger NK cell-mediated tumor cell killing via induction of the surface expression of ligands for the activating receptor NKG2D (NKG2D-L) on tumor cells, while reducing its soluble inhibitory ligands [109] [110,111]. In vitro data revealed that the treatment of PDAC cells with histone deacetylase inhibitors induced the NKG2D-L surface expression rendering the cells more susceptible to NK cell-killing [112]. In general, the administration of NK cell-based immunotherapy against pancreatic cancer has delivered promising results.…”

“…Instead, PMNs are thought to promote tumor progression such that high neutrophil counts correlate with poor patient prognoses. In clinical studies with PDAC patients, a neutrophil-lymphocyte ratio (NLR) was initially assessed as a predictive parameter; however, the diagnostic value of this ratio with regard to prognosis and survival prediction is controversial [112][113][114][115][116][117]. All of these studies are based on the assumption that PMNs can promote pancreatic tumor progression so that high PMN numbers in the tumor microenvironment (TME) correlate with a tumor-progressing state.…”

Natural killer cells in pancreatic cancer stroma

“…Similarly, the oncoprotein Sloan-Kettering Institute has been shown to inhibit SMAD association with the acetyltransferases CBP and p300, which are key regulators of inducible expression of NKG2D ligands on cancer cells, and facilitate repression of gene transcription via histone deacetylases. This results in downregulation of NKG2D ligands on tumoral cells, reducing NKG2D dependent cytotoxicity and facilitating immune evasion[ 53 ]. In addition, tumoral cells are seen to exhibit intricate crosstalk with NK effector cells and have been shown to induce functional deregulation[ 54 ].…”

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

“…In addition to a modulation of pro-and anti-apoptotic proteins, structurally divergent HDACi alter cytoskeletal organization and a dysregulation of energy control, nucleotide metabolism, and DNA repair protein expression [17,[20][21][22]. Moreover, the FDA-approved HDACi panobinostat and valproic acid promote the killing of PDAC cells by natural killer cells [23].…”