Malignant transformation of cells is frequently associated with HLA Class I antigens down-regulation. This abnormality appears to have clinical significance, since it is associated with histo-pathological markers of poor prognosis and with reduced disease free interval or survival in some malignancies. This association is likely to reflect the resistance of malignant cells with HLA abnormalities to HLA Class I restricted, tumor associated antigen (TAA) specific CTL. Hepatocellular carcinoma (HCC) differs from other types of malignancies in two respects. First, normal hepatocytes express a barely detectable level of HLA class I antigens. Second, analysis of a small number of HCC lesions has shown that malignant transformation of hepatocytes may be associated with increased HLA class I antigen expression. The reason for low HLA class I antigen expression by normal hepatocytes, the frequency of HLA class I antigen appearance in HCC lesions, the role played by the antigen processing machinery in these phenotypic changes, the frequency of HLA class I antigen loss because of loss of heterozygosity (LOH) and the impact of these HLA antigenic phenotypic changes on the clinical course of the disease are not known. Therefore, we will test the hypothesis that low HLA class I antigen expression by hepatocytes reflects downregulation of TAP and/or tapasin, two components of the antigen processing machinery. Furthermore, we will determine the frequency of HLA class I antigen appearance in HCC lesions and we will test the hypothesis that this antigenic change reflects an upregulation of TAP and/or tapasin in malignant hepatocytes. Third, we will test the hypothesis that selective HLA class I antigen loss occurs in HCC lesions, since a high frequency of LOH involving chromosome 6 has been described in HCC lesions. Chromosome 6 carries the genes encoding HLA class I heavy chains, Lastly, we will assess the clinical significance of HLA class I antigenic changes in HCC lesions by correlating them with clinical parameters. Since the frequency of HCC is much high in P.R. China than in the U.S.A., a collaboration has been established with Dr. Wei Xie, Nanjing, P.R. China. This collaboration is expected to greatly facilitate the analysis of a large number of HCC samples in a short time and to take advantage of Dr. Soldano Ferrone's expertise in analyzing HLA class I antigen expression by malignant cells and of the reagents he has developed.
