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Immunoglobulin framework-derived peptides function as cytotoxic T-cell epitopes commonly expressed in B-cell malignancies

Nature Medicine volume 6, pages 667–672 (2000)Cite this article

Abstract

Although the idiotypic structures of immunoglobulin from malignant B cells were the first tumor-specific determinants recognized, and clinical vaccination trials have demonstrated induction of tumor-specific immunity, the function of immunoglobulin-specific CD8+ cytotoxic T lymphocytes in tumor rejection remains elusive. Here, we combined bioinformatics and a T cell-expansion system to identify human immunoglobulin-derived peptides capable of inducing cytotoxic T-lymphocyte responses. Immunogenic peptides were derived from framework regions of the variable regions of the immunoglobulin that were shared among patients. Human-leukocyte-antigen-matched and autologous cytotoxic T lymphocytes specific for these peptides killed primary malignant B cells, demonstrating that malignant B cells are capable of processing and presenting such peptides. Targeting shared peptides to induce T-cell responses might further improve current vaccination strategies in B-cell malignancies.

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Figure 1: Patients, sequences obtained from clonal malignant B cells of those patients, and the peptides derived from the patients' immunoglobulins predicted to bind to HLA-A2 with a half-life of more than 1 min.
Figure 2: Generation of cytotoxic T cells against immunoglobulin-derived peptides that bind to HLA-A2.
Figure 3: Recognition of malignant B cells by HLA-matched and autologous CTLs raised against immunoglobulin-derived peptides.
Figure 4: Enhanced recognition of malignant B cells by peptide pulsing or CD40 activation of the malignant B cells.
Figure 5: CTLs raised against heteroclitic peptides of framework region derived peptides recognized the native peptide pulsed onto HLA-A2-positive antigen-presenting cells and tumor cells.

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Acknowledgements

We thank L.M. Nadler, C. Janeway Jr., K.W. Wucherpfennig and K.S. Anderson for reading the manuscript. We thank G. Dranoff for discussions and D. Neuberg for statistical assistance. Technical assistance for immunoglobulin sequencing was provided by T. Poor and D. Bowers, and for T-cell cultures, by M. Bedor and D. Schnipper. This work was supported by grants PO1 CA 66996, CA78378 and CA81534 from the National Institutes of Health. J.L.S. is a Special Fellow of the Leukemia and Lymphoma Society of America. M.W. is supported by a grant from the Deutsche Krebshilfe und Dr. Mildred Scheel Stiftung. R.H.V. is supported by a grant from the Doris Duke Charitable Foundation.

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Author notes

  1. Andreas Trojan and Joachim L. Schultze: A.T. and J.L.S. contributed equally to this study.

Authors and Affiliations

  1. Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, 02115, USA

    Andreas Trojan, Joachim L. Schultze, Mathias Witzens, Robert H. Vonderheide, Marco Ladetto, John W. Donovan & John G. Gribben

  2. Department of Medicine, Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts, 02115, USA

    Andreas Trojan, Joachim L. Schultze, Mathias Witzens, Robert H. Vonderheide, Marco Ladetto, John W. Donovan & John G. Gribben

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Correspondence to John G. Gribben.

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Trojan, A., Schultze, J., Witzens, M. et al. Immunoglobulin framework-derived peptides function as cytotoxic T-cell epitopes commonly expressed in B-cell malignancies. Nat Med 6, 667–672 (2000). https://doi.org/10.1038/76243

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