Molecular regulation of NK cell cytotoxicity fir human hepatocellular carcinoma

NK细胞对人肝细胞癌细胞毒性的分子调控

基本信息

批准号：
18390216
负责人：
TAKEHARA Tetsuo
金额：
$ 7.58万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390216/
关键词：
MICA NKG2D HCC NK receptor Liver Tumor Innate immunity MICB TAE 自然免 MICB Soluble MICA Soluble MICB

项目摘要

Soluble forms of MHC class I-related chain A and B (MICA/B) increase in sera of patients with malignancy and impair the anti-tumor immune response by downregulating expression of their cognate immunoreceptor NKG2D. Recently, soluble MICA/B were reported to appear even in some premalignant diseases, raising the question about the impact of soluble MICA/B produced from tumors on the expression of NKG2D. The present study examined soluble MICA/B in chronic liver disease and hepatocellular carcinoma (HCC) and their involvement in the immune cell expression of NKG2D during transcatheter arterial embolization (TAE) for HCC. The levels of soluble MICA/B were significantly higher in chronic liver disease and HCC patients than in healthy volunteers. The progression of liver disease and that of the tumor were independent determinants for soluble MICA/B levels. Immunohistochemistry revealed that MICA/B was expressed not only in HCC tissue but also on hepatocytes in cirrhotic livers. The TAE therapy significantly decreased serum levels of soluble MICA, but not soluble MICB, and increased the NKG2D expression on NK cells and CD8-positive T cells; there was an inverse correlation between changes in soluble MICA levels and in NKG2D expression. In vitro experiments confirmed that MICA-containing sera clearly downregulated NKG2D expression and suppressed NKG2D-mediated effector cell function. In conclusion, although soluble MICA/B are produced from both HCC and premalignant cirrhotic livers, therapeutic intervention for HCC can reduce the levels of soluble MICA and thereby upregulate the expression of NKG2D. Cancer therapy may have a beneficial effect on the NKG2D-mediated anti-tumor immunity.

MHC I类相关链A和B（云母/B）的可溶性形式通过下调其同源免疫受体NKG2D的表达来损害抗肿瘤免疫反应的血清。最近，据报道，甚至在某些预抗疾病中也出现了可溶性云母，这提出了有关肿瘤对NKG2D表达产生的可溶性云母/B的影响的问题。本研究检查了在经导管动脉栓塞（TAE）期间，在慢性肝病和肝细胞癌（HCC）中检查了可溶性云母/B及其参与NKG2D的免疫细胞表达。在慢性肝病和HCC患者中，可溶性云母/B的水平明显高于健康志愿者。肝病的进展和肿瘤的进展是可溶性云/B水平的独立决定因素。免疫组织化学表明，云母不仅在HCC组织中，而且在肝硬化肝中的肝细胞上表达。 TAE治疗显着降低了可溶性云母的血清水平，但不能显着降低可溶性MICB，并增加了NK细胞和CD8阳性T细胞上NKG2D的表达。可溶性云母水平的变化与NKG2D表达之间存在逆相关性。体外实验证实，含云母的血清清楚地下调了NKG2D表达，并抑制了NKG2D介导的效应细胞功能。总之，尽管可溶性云母/B是由HCC和前粘液性肝肝产生的，但HCC的治疗干预可以降低可溶性云母的水平，从而上调NKG2D的表达。癌症治疗可能对NKG2D介导的抗肿瘤免疫有益作用。