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CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy

Nature Medicine volume 5, pages 774–779 (1999)Cite this article

Abstract

The outcome of antigen recognition by naive CD8+ cytotoxic T lymphocytes (CTLs) in the periphery is orchestrated by CD4+ T-helper cells, and can either lead to priming or tolerization. The presence of T-helper cells favors the induction of CTL immunity, whereas the absence of T-helper cells can result in CTL tolerance. The action of T helper cells in CTL priming is mediated by CD40–CD40 ligand interactions. We demonstrate here that triggering of CD40 in vivo can considerably enhance the efficacy of peptide-based anti-tumor vaccines. The combination of a tolerogenic peptide vaccine containing a minimal essential CTL epitope with an activating antibody against CD40 converts tolerization into strong CTL priming. Moreover, CD40 ligation can provide an already protective tumor-specific peptide vaccine with the capacity to induce therapeutic CTL immunity in tumor-bearing mice. These findings indicate that the CD40–CD40 ligand pair can act as a 'switch', determining whether naive peripheral CTLs are primed or tolerized, and support the clinical use of CD40-stimulating agents as components of anti-cancer vaccines.

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Figure 1: Mice injected with the E1A peptide are no longer able to mount E1A-specific CTLs.
Figure 2: Tolerizing E1A peptide is rapidly distributed systemically after subcutaneous injection in IFA.
Figure 3: CTL tolerance induction is reverted to priming of CTLs after triggering of CD40 in vivo.
Figure 4: E1A-specific CD8+ cells can only be detected in the spleen after E1A peptide administration in combination with triggering of CD40.
Figure 5: B cells are not required for the induction of CTL tolerance after peptide administration.
Figure 6: B cells are not required for the restoration of CTL responses through CD40 activation.
Figure 7: Treatment of HPV16 E6- and E7-transformed cells by a combination of peptide together with in vivo CD40 triggering.

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Acknowledgements

We thank F. Claas for critically reading our manuscript and A.H. Zwinderman for statistical analysis. The research of R.E.M.T. was made possible by a fellowship of the Royal Academy of Arts and Sciences. This work was supported by the Dutch Cancer Foundation (grants RUL 97-1449 and RUL-97-1450). S.P.S is supported by a grant from the American Cancer Society.

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Authors and Affiliations

  1. Department of Immunohematology and Bloodbank, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, the Netherlands

    Linda Diehl, Annemieke Th. den Boer, Ellen I.H. van der Voort, Cornelis J.M. Melief, Rienk Offringa & Rene E. M. Toes

  2. Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, 92121, California, USA

    Stephen P. Schoenberger

  3. Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam

    Ton N.M. Schumacher

  4. Department of Immunology, Eberhart-Karls University, Auf der Morgenstelle 15, D-72076, Tübingen, Germany

    Rene E. M. Toes

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Correspondence to Rene E. M. Toes.

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Diehl, L., den Boer, A., Schoenberger, S. et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 5, 774–779 (1999). https://doi.org/10.1038/10495

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