The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC.
The Oncoprotein SKI Acts as A Suppressor of NK Cell-Mediated Immunosurveillance in PDAC.
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DOI：
10.3390/cancers12102857
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发表时间：
2020-10-03
期刊：
影响因子：
5.2
通讯作者：
Pogge von Strandmann E
中科院分区：
文献类型：
--
作者：
Ponath V;Frech M;Bittermann M;Al Khayer R;Neubauer A;Brendel C;Pogge von Strandmann E
胰腺导管腺癌是最致命的实体瘤之一，在过去的几十年里生存率没有显着提高。该疾病的特点是免疫抑制性肿瘤微环境，导致对新型免疫疗法的反应有限。我们研究的目的是帮助更好地了解胰腺癌中自然杀伤 (NK) 细胞活性的减弱。我们发现，参与 CBP/p300 介导的乙酰化的癌蛋白 SKI 减少了肿瘤细胞上细胞毒性受体 NKG2D 激活配体的表达，从而抵消了 NK 细胞依赖性细胞毒性。用组蛋白脱乙酰酶抑制剂 (HDACi) 处理肿瘤细胞可诱导这些配体的表达并改善 NK 细胞依赖性杀伤。因此，我们揭示了 SKI 在 NK 细胞介导的免疫监视中迄今为止未知的作用。我们的结果表明，HDACi 与基于 NK 细胞的免疫疗法相结合可能对胰腺癌患者有益。针对表观遗传机制的药物，例如组蛋白脱乙酰酶抑制剂 (HDACi)，可抑制肿瘤生长。 HDACi 还诱导细胞毒性受体 NKG2D 配体的表达，使肿瘤更容易受到自然杀伤 (NK) 细胞依赖性杀伤。负责 NKG2D 配体 (NKG2D-L) 表达的主要乙酰化酶是 CBP 和 p300。癌基因和转录抑制因子 SKI 的作用尚不清楚，SKI 是 HDAC 募集共抑制因子复合物的重要组成部分，在 TGFβ 信号传导中与 CBP/p300 竞争与 SMAD3 的结合。在这里，我们表明，在胰腺癌细胞系 Panc-1 和 Patu8988t 中，siRNA 介导的 SKI 下调导致原代 NK 细胞对靶细胞的杀伤增加。然而，NK 细胞的较高细胞毒性与 NKG2D-L 的诱导并不相关。值得注意的是，无论 SKI 表达水平如何，LBH589（LBH，帕比司他）或丙戊酸（VPA）治疗都可以诱导 NKG2D-L 的表达以及随后的 NK 细胞依赖性杀伤，但在 SKI 基因消除后，胰腺癌细胞中的 NKG2D-L 表达显着升高。这些数据表明 SKI 抑制 NKG2D-L 的诱导型表达。 HDACi 与基于 NK 细胞的免疫疗法的结合是胰腺肿瘤的一种有吸引力的治疗选择，特别是对于 SKI 蛋白水平高的患者。
Pancreatic 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.
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影响因子：
14.9
作者：
Feld C;Sahu P;Frech M;Finkernagel F;Nist A;Stiewe T;Bauer UM;Neubauer A
通讯作者：
Neubauer A
影响因子：
56.9
作者：
Bauer, S;Groh, V;Spies, T
通讯作者：
Spies, T
胰腺癌的表观遗传治疗：地平线上是否有治疗视角？
影响因子：
24.5
作者：
Hessmann E;Johnsen SA;Siveke JT;Ellenrieder V
通讯作者：
Ellenrieder V
丙戊酸通过通过PI3K/AKT信号通路上调云母和MICB，使胰腺癌细胞对天然杀伤细胞介导的裂解敏感。
影响因子：
3.8
作者：
Shi P;Yin T;Zhou F;Cui P;Gou S;Wang C
通讯作者：
Wang C
DOI：
10.1097/cji.0b013e31820e1b0d
发表时间：
2011-04
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Huang B;Sikorski R;Sampath P;Thorne SH
通讯作者：
Thorne SH