Armeanu Sorin, Krusch Matthias, Baltz Katrin M, Weiss Thomas S, Smirnow Irina, Steinle Alexander, Lauer Ulrich M, Bitzer Michael, Salih Helmut R
Department of Gastroenterology and Hepatology, Medical University Hospital, Tübingen, Germany.
Clin Cancer Res. 2008 Jun 1;14(11):3520-8. doi: 10.1158/1078-0432.CCR-07-4744.
Hepatocellular carcinoma (HCC) displays particular resistance to conventional cytostatic agents. Alternative treatment strategies focus on novel substances exhibiting antineoplastic and/or immunomodulatory activity enhancing for example natural killer (NK) cell antitumor reactivity. However, tumor-associated ligands engaging activating NK cell receptors are largely unknown. Exceptions are NKG2D ligands (NKG2DL) of the MHC class I-related chain and UL16-binding protein families, which potently stimulate NK cell responses. We studied the consequences of proteasome inhibition with regard to direct and NK cell-mediated effects against HCC.
Primary human hepatocytes (PHH) from different donors, hepatoma cell lines, and NK cells were exposed to Bortezomib. Growth and viability of the different cells, and immunomodulatory effects including alterations of NKG2DL expression on hepatoma cells, specific induction of NK cell cytotoxicity and IFN-gamma production were investigated.
Bortezomib treatment inhibited hepatoma cell growth with IC(50) values between 2.4 and 7.7 nmol/L. These low doses increased MICA/B mRNA levels, resulting in an increase of total and cell surface protein expression in hepatoma cells, thus stimulating cytotoxicity and IFN-gamma production of cocultured NK cells. Importantly, although NK cell IFN-gamma production was concentration-dependently reduced, low-dose Bortezomib neither induced NKG2DL expression or cell death in PHH nor altered NK cell cytotoxicity.
Low-dose Bortezomib mediates a specific dual antitumor effect in HCC by inhibiting tumor cell proliferation and priming hepatoma cells for NK cell antitumor reactivity. Our data suggest that patients with HCC may benefit from Bortezomib treatment combined with immunotherapeutic approaches such as adoptive NK cell transfer taking advantage of enhanced NKG2D-mediated antitumor immunity.
肝细胞癌（HCC）对传统细胞抑制剂表现出特殊的抗性。替代治疗策略聚焦于具有抗肿瘤和/或免疫调节活性的新型物质，例如增强自然杀伤（NK）细胞抗肿瘤反应性。然而，与激活NK细胞受体结合的肿瘤相关配体在很大程度上尚不明确。MHC I类相关链和UL16结合蛋白家族的NKG2D配体（NKG2DL）是例外，它们能有效刺激NK细胞反应。我们研究了蛋白酶体抑制对HCC的直接和NK细胞介导作用的影响。
将来自不同供体的原代人肝细胞（PHH）、肝癌细胞系和NK细胞暴露于硼替佐米。研究不同细胞的生长和活力，以及免疫调节作用，包括肝癌细胞上NKG2DL表达的改变、NK细胞细胞毒性的特异性诱导和IFN-γ产生。
硼替佐米治疗抑制肝癌细胞生长，IC50值在2.4至7.7 nmol/L之间。这些低剂量增加了MICA/B mRNA水平，导致肝癌细胞中总蛋白和细胞表面蛋白表达增加，从而刺激共培养NK细胞的细胞毒性和IFN-γ产生。重要的是，尽管NK细胞IFN-γ产生呈浓度依赖性降低，但低剂量硼替佐米既未诱导PHH中NKG2DL表达或细胞死亡，也未改变NK细胞细胞毒性。
低剂量硼替佐米通过抑制肿瘤细胞增殖和使肝癌细胞对NK细胞抗肿瘤反应致敏，在HCC中介导特异性双重抗肿瘤作用。我们的数据表明，HCC患者可能受益于硼替佐米治疗与免疫治疗方法（如利用增强的NKG2D介导的抗肿瘤免疫的过继性NK细胞转移）相结合。
