Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model
Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model
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DOI：
10.3892/ijo_00000387
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发表时间：
2009-10-01
影响因子：
5.2
通讯作者：
Miura, Soichiro
中科院分区：
文献类型：
--
作者：
Okudaira, Keisuke;Hokari, Ryota;Miura, Soichiro
程序性死亡-1（PD-1）及其配体B7-H1和B7-DC相互作用所提供的负信号在肿瘤逃避宿主免疫中起重要作用。B7-H1表达的胰腺癌患者预后差。B7-H1阻断已显示抑制胰腺癌细胞系的皮下肿瘤的发展。在这项研究中，我们研究了B7-DC以及B7-H1阻断剂在小鼠胰腺癌模型中的体内作用。将胰腺癌细胞（Panc02）接种在C57BL/6小鼠的胰腺中。五周后，测量肿瘤大小，并且携带适当大小肿瘤的小鼠接受以下治疗。抗B7-H1或B7-DC的阻断抗体（200 μ g）每周给药3次，持续3周。浸润肿瘤的细胞通过免疫组织化学表征。通过定量RT-PCR检测抗体对细胞因子和FoxP3表达的影响。体外培养的Panc02细胞在IFN-γ刺激后表达B7-H1。然而，B7-H1和B7-DC的表达主要见于CD45阳性的浸润细胞，很少见于体内癌细胞。用两种抗体治疗显著降低体内肿瘤生长。B7-DC阻断降低了IL-10和FoxP3的水平，表明调节系统主要在肿瘤部位受到抑制。B7-H1阻断增加IFN-γ和FoxP3的水平。总的来说，阻断B7-H1或B7-DC通过上调肿瘤部位的IFN-γ产生和下调IL-10产生而有效地诱导预先建立的胰腺癌的消退。
The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, B7-H1 and B7-DC, has been suggested to play an important role in tumor evasion from host immunity. Pancreas cancer patients with B7-H1 expression have a poor prognosis. B7-H1 blocking has been shown to inhibit the development of a subcutaneous tumor from a pancreas cancer cell line. In this study, we investigated the effects of B7-DC as well as B7-H1 blockade in vivo in a murine pancreatic cancer model. Pancreatic cancer cells (Panc02) were inoculated in the pancreas of C57BL/6 mice. Five weeks later, tumor sizes were measured and the mice bearing appropriate size of tumors received the following treatments. Blocking antibodies against B7-H1 or B7-DC (200 mu g) were administered 3 times/week for 3 weeks. Cells infiltrating the tumors were characterized by immunohistochemistry. Effects of antibodies on cytokine and FoxP3 expression were examined by quantitative RT-PCR. In vitro cultured Panc02 cells expressed B7-H1 upon IFN-gamma stimulation. However, expression of B7-H1 and B7-DC was found mainly on CD45-positive infiltrating cells and rarely on cancer cells in vivo. Treatment with both antibodies significantly decreased tumor growth in vivo. B7-DC blockade decreased the levels of IL-10 and FoxP3, suggesting that regulatory systems are mainly inhibited at the tumor site. B7-H1 blockade increased the levels of IFN-gamma and FoxP3. Collectively, blocking of B7-H1 or B7-DC efficiently induced regression of pre-established pancreatic cancers by up-regulating IFN-gamma production and down-regulating IL-10 production at the tumor site.