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Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer

Nature Immunology volume 2, pages 962–970 (2001)Cite this article

Abstract

We identified a tumor-associated cytotoxic T lymphocyte (CTL) epitope derived from the widely expressed human MDM2 oncoprotein and were able to bypass self-tolerance to this tumor antigen in HLA-A*0201 (A2.1) transgenic mice and by generating A2.1-negative, allo-A2.1–restricted human T lymphocytes. A broad range of malignant, as opposed to nontransformed cells, were killed by high-avidity transgenic mouse and allogeneic human CTLs specific for the A2.1-presented MDM2 epitope. Whereas the self-A2.1–restricted human T cell repertoire gave rise only to low-avidity CTLs unable to recognize the natural MDM2 peptide, human A2.1+ T lymphocytes were turned into efficient MDM2-specific CTLs upon expression of wild-type and partially humanized high-affinity T cell antigen receptor (TCR) genes derived from the transgenic mice. These results demonstrate that TCR gene transfer can be used to circumvent self-tolerance of autologous T lymphocytes to universal tumor antigens and thus provide the basis for a TCR gene transfer–based broad-spectrum immunotherapy of malignant disease.

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Figure 1: Efficiency and specificity of CTLs derived from CD8×A2Kb Tg mice and reactive to MDM2(81–88) peptide.
Figure 2: The MDM2(81–88) peptide is a naturally processed CTL epitope.
Figure 3: The MDM2(81–88) peptide is a universal tumor- and leukemia-associated CTL epitope.
Figure 4: The self-A2.1–restricted human T cell repertoire is devoid of high-avidity MDM2(81–88)-specific CTLs.
Figure 5: Bypassing MDM2-specific self-tolerance by allo-A2.1–restricted human CTLs.
Figure 6: Delivering MDM2-specific TCRs into human T lymphocytes.

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Acknowledgements

We thank E. Antunes Ferreira, U. Brass, A. Heit and U. Liewer (JGU) for contributing to this study, and M. Jülch (JGU) for flow cytometric analyses. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 432 A3) (to M. T.), the Stiftung Rheinland-Pfalz für Innovation (to M. T.), the MAIFOR program (to J. K. and to M. T.), the Leukemia Research Fund (to H. J. S.), the Cancer Research Campaign (to H. J. S.) and the Medical Research Council (to H. J. S.).

Author information

Author notes

  1. Elena Sadovnikova

    Present address: National Center for Hematology, 125167, Moscow, Russia

  2. Thomas Ruppert

    Present address: Zentrum für Molekulare Biologie, Ruprecht-Karls University, D-69120, Heidelberg, Germany

  3. Thomas Stanislawski and Ralf-Holger Voss: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, Johannes Gutenberg University, Mainz, D-55101, Germany

    Thomas Stanislawski, Ralf-Holger Voss, Carina Lotz, Jürgen Kuball, Christoph Huber & Matthias Theobald

  2. Department of Immunology, Hammersmith Hospital, Imperial College School of Medicine, London, W12 0NN, UK

    Elena Sadovnikova & Hans J. Stauss

  3. Department of Clinical and Tumor Immunology, Daniel den Hoed Cancer Center, Rotterdam, 3075 EA, The Netherlands

    Ralph A. Willemsen & Reinder L. H. Bolhuis

  4. Max von Pettenkofer Institute for Virology, Ludwig Maximilians University, Munich, D-80336, Germany

    Thomas Ruppert

  5. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands

    Cornelius J. Melief

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Correspondence to Matthias Theobald.

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Stanislawski, T., Voss, RH., Lotz, C. et al. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2, 962–970 (2001). https://doi.org/10.1038/ni1001-962

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