BETA(2)-MICROGLOBULIN GENE-MUTATIONS IN HUMAN-MELANOMA CELLS - MOLECULAR CHARACTERIZATION AND IMPLICATIONS FOR IMMUNE SURVEILLANCE

In recent years, the mechanisms underlying defects in the expression/f unction of human leukocyte antigen (HLA) class I antigens have been an alyzed in an increasing number of melanoma cells,since these abnormali ties are likely to have a negative impact on T-cell-based immunotherap y of melanoma. This article reviews the information about the molecula r defects found in melanoma cell lines that do not express HLA class I antigens, following a concise description of the structure and assemb ly of HLA class I antigens. Distinct defects ranging from large deleti ons to point mutations in beta(2)-microglobulin genes have been found in melanoma cells. A mutation in an 8 base-pair CT repeat region of ex on 1 has been found frequently in melanoma cell lines suggesting that this region of the beta(2)-microglobulin gene is a hot-spot for mutati ons. The effects of beta(2)-microglobulin mutations are mostly at the level of translation, emphasizing the importance of analyzing beta(2)- microglobulin expression at the protein level in melanoma lesions with out detectable HLA class I antigen expression. Interestingly, many mel anoma cell lines have additional defects that directly impact HLA clas s I antigen expression. Therefore, multiple mechanisms that affect the expression/function of HLA class I antigens appear to be available to melanoma cells to escape from immune recognition.