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TAP expression provides a general method for improving the recognition of malignant cells in vivo

Nature Biotechnology volume 18, pages 515–520 (2000)Cite this article

Abstract

A major class of tumors lack expression of the transporters associated with antigen processing (TAP). These proteins are essential for delivery of antigenic peptides into the lumen of the endoplasmic reticulum (ER) and subsequent assembly with nascent major histocompatibility complex (MHC) class I, which results in cell surface presentation of the trimeric complex to cytolytic T lymphocytes. Cytolytic T lymphocytes are major effector cells in immunosurveillance against tumors. Here we have tested the hypothesis that TAP downregulation in tumors allows immunosubversion of this effector mechanism, by establishing a model system to examine the role of TAP in vivo in restoring antigen presentation, immune recognition, and effects on malignancy of the TAP-deficient small-cell lung carcinoma, CMT.64. To test the potential of providing exogenous TAP in cancer therapies, we constructed a vaccinia virus (VV) containing the TAP1 gene and examined whether VV-TAP1 could reduce tumors in mice. The results demonstrate that TAP should be considered for inclusion in cancer therapies, as it is likely to provide a general method for increasing immune responses against tumors regardless of the antigenic complement of the tumor or the MHC haplotypes of the host.

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Figure 1: Increase of CMT.64 antigenicity by transfection with TAP1 but not TAP2.
Figure 2: Control of tumor growth in vivo and improvement of mice survival by introducing rTAP heterodimer or rTAP1 but not rTAP2 into CMT.64 tumor cell line.
Figure 3: TAP1 expression within growing tumors in mice.
Figure 4: Examination of the survival of mice bearing CMT tumors.
Figure 5: Antitumor immune therapy by VV-rTAP1.

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Acknowledgements

We would like to thank Bernard Moss, John Yewdell, Sun Kvist, and Geoff Butcher for their generosity in providing reagents for this work. We would also like to thank the Jefferies lab for support and for reviewing the manuscript. Finally we acknowledge support from the MRC of Canada and the National Cancer Institute of Canada.

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Author notes

  1. Judy Alimonti and Qian-Jin Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Biomedical Research Centre and the Departments of Medical Genetics, The Biotechnology Laboratory, Microbiology and Immunology, and Zoology, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC V6T 1Z3, Canada

    Reinhard Gabathuler, Gregor Reid, Susan S. Chen & Wilfred A. Jefferies

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  1. Judy Alimonti
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  2. Qian-Jin Zhang
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  3. Reinhard Gabathuler
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  4. Gregor Reid
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  5. Susan S. Chen
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  6. Wilfred A. Jefferies
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Correspondence to Wilfred A. Jefferies.

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Alimonti, J., Zhang, QJ., Gabathuler, R. et al. TAP expression provides a general method for improving the recognition of malignant cells in vivo. Nat Biotechnol 18, 515–520 (2000). https://doi.org/10.1038/75373

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