肝癌细胞通过选择性调节HLA I 类等位基因表达逃逸NK细胞和CTL的双重免疫监视机制研究

经典HLA I类分子在NK细胞和CTL活性的调节中均发挥了关键作用，且不同等位基因编码的分子作用不同。在白血病中的发现支持肿瘤细胞在面临NK细胞与CTL的双重免疫压力时能选择性调节HLA等位基因的表达而实现免疫逃逸。肝脏中NK细胞与CTL的数量相当，肝癌细胞必须同时逃逸NK细胞和CTL的双重免疫监视。本研究的预实验结果发现肝癌中确实存在着HLA等位基因的差异性表达现象，推测肝癌细胞很可能也通过选择性调节HLA等位基因的表达而同时逃逸NK细胞和CTL的杀伤。本项目拟对肝癌患者的HLA-A/-B/-C位点和KIR位点进行基因分型,检测肝癌组织中以上HLA位点各等位基因的表达水平，明确其中是否存在HLA I 类等位基因选择性的异常表达，并分析基因多态性、分子异常表达模式与患者的临床表现及预后之间的相关性。本研究拟探索肝癌免疫逃逸的新机制，同时能够为发展基于NK细胞的肝癌的免疫治疗提供实验依据。

Classical human leukocyte antigen (HLA) class I molecules play critical role in both natural killer (NK) cell and cytotoxicity T lymphocyte (CTL) regulation through direct binding, and products of various HLA class I alleles have different functions in these process. Loss/downregulation of HLA class I is a frequent event associated with tumor development. However, the expression of HLA class I was found upregulated in majority liver cancer tissues. Findings observed in leukemia indicated that tumor cell could selectively modulate expressions of HLA class I alleles to escape from killing of both NK cell and CTL. In liver tissue, NK cells are abundant, so tumor cells in liver have to escape surveillance from both NK cells and CTLs. Our early study suggests that liver tumor cells may also selectively modulate expressions of HLA class I alleles to escape surveillance from both NK cells and CTLs as leukemia cells do. To test this hypothesis, we will genotype HLA class I and killer cell immunoglobulin-like receptors of liver cancer patients, detect the expression level of each HLA class I allele in liver tumor tissues and adjacent normal tissues， and explore the association of genetic background, aberrant expression pattern of HLA I allelles between clinical manifestation and prognosis of liver cancer patients. This project may not only discover a novel mechanism underlying immune escape of liver cancer, but also provide basis for NK cell therapy for liver cancer.