Molecular regulation of NK cell cytotoxicity fir human hepatocellular carcinoma

可溶性形式的MHC I类相关链A和B（云母/B）在恶性肿瘤患者血清中增加，并通过下调其同源免疫受体NKG 2D的表达而损害抗肿瘤免疫应答。最近，据报道，可溶性云母/B甚至出现在一些癌前疾病中，提出了关于肿瘤产生的可溶性云母/B对NKG 2D表达的影响的问题。本研究检测了慢性肝病和肝细胞癌（HCC）中可溶性云母/B及其在HCC经导管动脉栓塞（TAE）期间参与NKG 2D的免疫细胞表达。慢性肝病和HCC患者的可溶性云母/B水平显著高于健康志愿者。肝脏疾病和肿瘤的进展是可溶性云母/B水平的独立决定因素。免疫组化结果显示云母/B不仅在HCC组织中表达，而且在肝细胞中也有表达。TAE治疗显著降低了可溶性MICA的血清水平，但未降低可溶性MICB，并增加了NK细胞和CD 8阳性T细胞上的NKG 2D表达;可溶性云母水平的变化与NKG 2D表达之间呈负相关。体外实验证实，含MICA的血清明显下调NKG 2D表达并抑制NKG 2D介导的效应细胞功能。总之，尽管可溶性云母/B由HCC和癌前病变肝脏产生，但HCC的治疗干预可降低可溶性云母的水平，从而上调NKG 2D的表达。癌症治疗可能对NKG 2D介导的抗肿瘤免疫产生有益影响。

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.