The Mechanism Of HLA Class I And Correlative Molecules Expressed Abnormally In Gastric Cancer

Pathogenesis of tumors and anti-tumor immune response in host has attracted a lot of attention. HLA class I molecules play a critical role in the antigen processing, presenting and special recognition of tumor cells by cytotoxic T lymphocytes (CTL). There is a general consensus that the abnormal expression of HLA class I molecules reflects the escape mechanism of tumor cells and it is pivotal to excite tumor antigen-special CTL to carry through immune therapy for the expression of HLA class I molecules in tumor cells surface. We discussed the expression of HLA class I molecules in gastric cancer tissues and detected the LOH of microsatellite DNA at HLA gene region, which provided a theory basis for studying the abnormal expression mechanism of HLA class I molecules in gastric cancer.185 formalin-fixed paraffin-embeded tumor tissues, 22 corresponding autologous normal specimens and 20 lymphnode metastatic cases were tested using 4 monoclonal antibodies (mAbs) by meanings of immunohistochemical technique (ABC method); 50 OCT-embeded fresh gastric cancer and corresponding normal tissues, which were made into freezing slice, were tested applying 5 monoclonal antibodies (mAbs) by the same method, and analyzed of the LOH frequency at HLA (6p) and β2m (15q) gene region by microsatellite polymorphic analysis technology.HLA class I antigens were obviously downregulated (A locus 41%, B/C locus 32%) and lost (A locus 22%, B/C locus 19%) in 185 formalin-fixed paraffin-embeded gastric cancer tissues, and the downregulated expression of B/C locus is significantly associated with pathological grade (p<0.05). In 20 lymphnode metastatic cases, 8 cases show downregulated expression of HLA class I antigens compared with the primary tumor. HLA class I antigens were also obviously downregulated in 50 OCT-embeded fresh gastric cancer compared with corresponding normal tissues (P<0.05). The downregulated expression is correlated with heavy chain molecules especially HLA-B/C locus. It was accordant to the results of the paraffin-embeded tissues. The LOH frequency of HLA gene region is 18.3% in gastric cancer and the highest is D6s105 (34.2%). The individual LOH frequency for the six intra-MHC markers was: D6S1618, 16%; D6S291, 12%; D6S273, 15%; D6S265, 15%; D6S105, 34%; D6S276, 16%. It was not seen about loss of the whole chromosome 6 in the studied samples. The LOH frequency of β2m gene is 14.5%. D15S-126 and D15S-209, next toβ2m, was 18% and 11% respectively.Our results indicate that expression of HLA class I antigens is obviously downregulated in gastric cancer, and which is more obvious in lymphnode metastatic cases than the primary tumor. The downregulation is correlated with heavy chain molecules(P<0.05 ). In order to elucidate the mechanism, we extended our study to detect LOH (loss of heterozigosity) of microsatellite DNA at HLA gene region in gastric cancer and compared HLA class I molecules expression with LOH in corresponding locus, the results indicate that the majority of the tumors with positive expression of HLA class I have no allelic loss at all informative loci, the tumors with weak or negative expression show LOH for at least one locus. However, it can be concluded that LOH of HLA class I heavy chains was one of the mechanisms that lead to abnormally expression of HLA class I molecules and provided the tumor cells with a way to escape immune surveillance in gastric cancer. But, it is not benefit for T-cell based treat of tumor.