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Identification of Mechanisms Underlying Transporter Associated with Antigen Processing Deficiency in Metastatic Murine Carcinomas

¹ Biomedical Research Centre and Michael Smith Laboratories, Department of Zoology, Medical Genetics, Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada and ² Lady Davis Institute of Medical Research, McGill University, Montreal, Quebec, Canada

Requests for reprints: Wilfred A. Jefferies, Biomedical Research Centre and Michael Smith Laboratories, University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Phone: 604-822-6961; Fax: 604-822-6780; E-mail: wilf{at}brc.ubc.ca.

Expression of transporter associated with antigen processing (TAP) is often lost in metastatic carcinomas, resulting in defective antigen processing and presentation and escape of the cancer cells from immune surveillance. In this study, the nature of TAP deficiencies in tumors was investigated. By chromatin immunoprecipitation assay, we showed that the recruitment of RNA polymerase II to the TAP-1 gene was impaired in TAP-deficient cells derived from murine melanoma, prostate, and lung carcinomas, compared with TAP-expressing fibroblasts and lymphoma cells. This suggested that the deficiency in TAP-1 expression resulted, at least partially, from a relatively low level of transcription of the TAP-1 gene. Furthermore, levels of TAP-1 promoter activity, as assessed by stable transfections with a reporter construct containing the TAP-1 promoter, were relatively low in TAP-deficient cells. To examine genetic heritability of regulators of TAP-1 promoter activity, TAP- and MHC class I–deficient cells of H-2^b origin were fused with wild-type fibroblasts of H-2^k origin. Fusion with TAP-expressing cells complemented the low levels of TAP-1 promoter activity in TAP-deficient cells. However, these fused cells exhibited lower levels of TAP-1 mRNA and H-2^k than unfused fibroblasts. Further analysis showed that TAP-1 mRNA stability was lower in fused carcinoma fibroblasts than in unfused fibroblasts. Based on these results, we propose that TAP deficiency in many carcinomas is caused by a decrease in activity/expression of trans-acting factors regulating TAP-1 promoter activity, as well as a decrease in TAP-1 mRNA stability. These results have significant implications for understanding immune evasion mechanisms in tumors.

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