Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg.

Andreas S. Baur, Manfred B. Lutz, Stephan Schierer, Luca Beltrame, Gabi Theiner, Elisabeth Zinser, Christian Ostalecki, Gordon Heidkamp, Ina Haendle, Michael Erdmann, Manuel Wiesinger, Waltraud Leisgang, Stefanie Gross, Ansgar J. Pommer, Eckhart Kämpgen, Diana Dudziak, Alexander Steinkasserer, Duccio Cavalieri, Beatrice Schuler-Thurner, Gerold Schuler

Research output: Contribution to journalArticle

Abstract

Denileukin diftitox (DD), a diphtheria toxin fragment IL-2 fusion protein, is thought to target and kill CD25(+) cells. It is approved for the treatment of cutaneous T-cell lymphoma and is used experimentally for the depletion of regulatory T cells (Treg) in cancer trials. Curiously enough, clinical effects of DD did not strictly correlate with CD25 expression, and Treg depletion was not confirmed unambiguously. Here, we report that patients with melanoma receiving DD immediately before a dendritic cell (DC) vaccine failed to develop a tumor-antigen-specific CD4 and CD8 T-cell immune response even after repeated vaccinations. Analyzing the underlying mechanism, so far we found unknown effects of DD. First, DD modulated DCs toward tolerance by downregulating costimulatory receptors such as CD83 and CD25 while upregulating tolerance-associated proteins/pathways including Stat-3, β-catenin, and class II transactivator-dependent antigen presentation. Second, DD blocked Stat3 phosphorylation in maturing DCs. Third, only activated, but not resting, Treg internalized DD and were killed. Conversely, resting Treg showed increased survival because of DD-mediated antiapoptotic IL-2 signaling. We conclude that DD exerts functions beyond CD25(+) cell killing that may affect their clinical use and could be tested for novel indications.

Original languageEnglish
Pages (from-to)2185-2194
Number of pages10
JournalBlood
Volume122
Issue number13
DOIs
Publication statusPublished - Sep 26 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Baur, A. S., Lutz, M. B., Schierer, S., Beltrame, L., Theiner, G., Zinser, E., Ostalecki, C., Heidkamp, G., Haendle, I., Erdmann, M., Wiesinger, M., Leisgang, W., Gross, S., Pommer, A. J., Kämpgen, E., Dudziak, D., Steinkasserer, A., Cavalieri, D., Schuler-Thurner, B., & Schuler, G. (2013). Denileukin diftitox (ONTAK) induces a tolerogenic phenotype in dendritic cells and stimulates survival of resting Treg. Blood, 122(13), 2185-2194. https://doi.org/10.1182/blood-2012-09-456988