Inefficient exogenous loading of a tapasin-dependent peptide onto HLA-B*44:02 can be improved by acid treatment or fixation of target cells

Authors

  • Vincent Stroobant,

    1. Ludwig Institute for Cancer Research, Brussels, Belgium
    2. WELBIO and de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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    • These authors contributed equally to the work.

  • Nathalie Demotte,

    1. Ludwig Institute for Cancer Research, Brussels, Belgium
    2. WELBIO and de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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    • These authors contributed equally to the work.

  • Rosalie M. Luiten,

    1. Department of Dermatology, Academic Medical Center, University of Amsterdam, The Netherlands
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  • Ralf M. Leonhardt,

    1. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
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  • Peter Cresswell,

    1. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
    2. Howard Hughes Medical Institute, Chevy Chase, MD, USA
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  • Aude Bonehill,

    1. Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of Vrije Universiteit Brussel (VUB), Brussels, Belgium
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  • Alexandre Michaux,

    1. Ludwig Institute for Cancer Research, Brussels, Belgium
    2. WELBIO and de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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  • Wenbin Ma,

    1. Ludwig Institute for Cancer Research, Brussels, Belgium
    2. WELBIO and de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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  • Arend Mulder,

    1. Department of Immunohematology, Leiden University Medical Center, Leiden, The Netherlands
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  • Benoît J. Van den Eynde,

    1. Ludwig Institute for Cancer Research, Brussels, Belgium
    2. WELBIO and de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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  • Pierre van der Bruggen,

    1. Ludwig Institute for Cancer Research, Brussels, Belgium
    2. WELBIO and de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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  • Nathalie Vigneron

    Corresponding author
    1. WELBIO and de Duve Institute, Université catholique de Louvain, Brussels, Belgium
    • Ludwig Institute for Cancer Research, Brussels, Belgium
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Correspondence: Dr. Nathalie Vigneron, Ludwig Institute for Cancer Research, de Duve Institute, Avenue Hippocrate 74, UCL 7459; B-1200 Brussels, Belgium

Fax: +32-27647590

e-mail: nathalie.vigneron@bru.licr.org

Abstract

Antitumor cytolytic T lymphocytes (CTLs) recognize peptides derived from cellular proteins and presented on MHC class I. One category of peptides recognized by these CTLs is derived from proteins encoded by “cancer-germline” genes, which are specifically expressed in tumors, and therefore represent optimal targets for cancer immunotherapy. Here, we identify an antigenic peptide, which is derived from the MAGE-A1-encoded protein (160-169) and presented to CTLs by HLA-B*44:02. Although this peptide is encoded by MAGE-A1, processed endogenously and presented by tumor cells, the corresponding synthetic peptide is hardly able to sensitize target cells to CTL recognition when pulsed exogenously. Endogenous processing and presentation of this peptide is strictly dependent on the presence of tapasin, which is believed to help peptide loading by stabilizing a peptide-receptive form of HLA-B*44:02. Exogenous loading of the peptide can be dramatically improved by paraformaldehyde fixation of surface molecules or by peptide loading at acidic pH. Either strategy allows efficient exogenous loading of the peptide, presumably by generating or stabilizing a peptide-receptive, empty conformation of the HLA. Altogether, our results indicate a potential drawback of short peptide-based vaccination strategies and offer possible solutions regarding the use of problematic epitopes such as the one described here.

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