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The Antigen Processing Machinery of Class I Human Leukocyte Antigens

Linked Patterns of Gene Expression in Neoplastic Cells¹

Laboratory of Immunology, Regina Elena Cancer Institute CRS, 00158 Rome [E. G., L. S., A. M., S. M., P. Gi.]; Medical Oncology II [I. V.] and Laboratory of Pathology [M. M.], Regina Elena Cancer Institute, and Dermatology/Oncology, S. Maria and S. Gallicano Institute [L. E., C. C.], Istituti Fisioterapici Ospitalieri, 00144 Rome; Department of Oncology and Genetics, University of Genoa, Laboratory of Immunogenetics, National Cancer Institute, Center for Advanced Biotechnology, 16132 Genoa [G. B. F.]; and Medical Genetics, University ‘La Sapienza,’ S. Camillo-Forlanini Hospital, 00149 Rome [S. C., P. Gr.], Italy

The ultimate outcome of an immune response (escape or surveillance) depends on a delicate balance of opposing signals delivered by activating and inhibitory immune receptors expressed by cytotoxic T lymphocytes and natural killer cells. In this light, loss and down-regulation of human leukocyte antigens (HLA) class I molecules, while important for keeping tumors below the T-cell detection levels, may incite recognition of missing self. Conversely, the maintenance of normal levels of expression (or even up-regulation) may be favorable to tumors, at least in certain cases. In this study, we took advantage of a previously characterized panel of 15 early passage tumor cell lines (mainly from melanoma and lung carcinoma lesions) enriched with class I-low phenotypes. These cells were systematically characterized by Northern and/or Western blotting (e.g., mini-transcriptome/mini-proteome analysis) for the expression of HLA-A, -B, -C, ß₂-microglobulin, and the members of the "antigen processing machinery" of class I molecules (LMP2, LMP7, TAP1, TAP2, tapasin, calreticulin, calnexin, and ERp57). In addition, we established four pairs of cultures, each comprising melanoma cells and normal melanocytes from the same patient. We found that 97% of the 185 tested gene products are expressed (although often weakly), and in many cases coordinately regulated in 18 of 19 tumor cell lines. Linked expression patterns could be hierarchically arranged by statistical methods and graphically described as a class I HLA "coordinome." Deviations (both down- and up-regulation) from the coordinome expression pattern inherited from the normal, paired melanocyte counterpart, were allowed but limited in magnitude, as if melanoma cells were trying to keep a "low profile" HLA phenotype. We conclude that irreversible HLA loss is a rare event, and class I expression in tumor cells almost invariably results from reversible gene regulatory (rather than gene disruption) events.

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