活化性受体NKG2D通过识别肿瘤细胞膜配体活化NK细胞，而肿瘤细胞可通过分泌可溶型NKG2D配体(MICA/B及ULBP1)而逃逸NK细胞的免疫攻击。NKG2D配体ULBP2的研究较少，尤其分泌型sULBP2与肝癌的免疫逃逸机制研究仍为空白。我们曾证实阻断肝细胞NKG2D膜型配体表达可大幅减缓NK细胞活化（黄玫等.Hepatology 2013），但是可溶型配体对NK细胞的作用仍然不明。我们初步的临床研究表明，HBV肝癌患者血清sULBP2与肝癌发展密切相关。本项目拟扩大病人病例并动态分析血清sULBP2与患者预后的相关性；进一步研究的重组表达的sULBP2蛋白在体外对人NK细胞系或新鲜NK细胞负调的分子机制；在肝癌裸鼠模型进行NK细胞转输治疗，以此模型验证sULBP2对NK细胞免疫治疗的负调作用，并寻找靶向拮抗sULBP2以提高NK细胞免疫治疗效应的可行性，为肝癌免疫治疗提供新的靶点。

Activating receptor NKG2D activate NK cells by interaction with its ligands expressed on tumor cells membrane, and tumor cells can escape immune attack from NK cells by secreting soluble NKG2D ligands, including MICA/B and ULBP1.However, there was few report about another NKG2D ligand, ULBP2, especially about soluble ULBP2(sULBP2) involvement in immune evasion mechanism of hepatocellular carcinoma. We have demonstrated that reduced expression of membrane NKG2D ligands on hepatocytes can inhibit NK cells activation significantly, but little is known about soluble NKG2D ligands relation with NK cells function. In our preliminary clinical study, we found that serum sULBP2 of HBV related HCC patients was closely related with HCC progression. The project intends to expand patient cases and analyze serum sULBP2 relation with HCC prognosis; and investigate recombinant sULBP2 regulation mechanism in human NK cell lines and fresh NK cells. Furtherly, we plan to carry out NK cells transfer therapy to nude mice with HCC xenografts, and validate sULBP2 negative effect on NK cells immune therapy in this model. We aim to confirm the feasibility of targeting ULBP2 to improve NK cells immunotherapy, which may provide a new target for immunotherapy of hepatocellular carcinoma.