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Exposure of CD34+ precursors to cytostatic anthraquinone-derivatives induces rapid dendritic cell differentiation: implications for cancer immunotherapy

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Abstract

Appropriate activation of dendritic cells (DC) is essential for successful active vaccination and induction of cell-mediated immunity. The scarcity of precursor cells, as well as long culture methods, have hampered wide-scale application of DC vaccines derived from CD34+ precursors, despite their suggested superior efficacy over the more commonly applied monocyte-derived DC (MoDC). Here, employing the CD34+/CD14+ AML-derived human DC progenitor cell line MUTZ3, we show that cytostatic anthraquinone-derivatives (i.e., the anthracenedione mitoxantrone and the related anthracyclin doxorubicin) induce rapid differentiation of CD34+ DC precursors into functional antigen-presenting cells (APC) in a three-day protocol. The drugs were found to act specifically on CD34+, and not on CD14+ DC precursors. Importantly, these observations were confirmed for primary CD34+ and CD14+ DC precursors from peripheral blood. Mitoxantrone-generated DC were fully differentiated within three days and after an additional 24 h of maturation, were as capable as standard 9-day differentiated and matured DC to migrate toward the lymph node-homing chemokines CCL19 and CCL21, to induce primary allogeneic T cell proliferation, and to prime functional MART1-specific CD8+ T lymphocytes. Our finding that anthraquinone-derivatives like mitoxantrone support rapid high-efficiency differentiation of DC precursors may have consequences for in vitro production of DC vaccines as well as for novel immunochemotherapy strategies.

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Acknowledgments

This work was supported by a grant from the Dutch Cancer Society: KWF2003-2830 to GLS, TDG and RJS.

Conflict of interest

DCPrime B.V. is a spin-off company from the Pathology Department at the VU University medical center, Amsterdam developing allogeneic DC vaccines for clinical use. AW Reurs, PGJTB Wijnands, S van Wetering, and AM Kruisbeek are employees, and the latter CEO of DCPrime B.V. RJ Scheper and AM Kruisbeek are co-founders of DCPrime B.V.

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Authors and Affiliations

  1. Department of Pathology, VU University Medical Center, de Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Rieneke van de Ven, Anneke W. Reurs, Pepijn G. J. T. B. Wijnands, Erik Hooijberg, George L. Scheffer & Rik J. Scheper

  2. Division of Immunotherapy, Medical Oncology Laboratory, VU University Medical Center, de Boelelaan 1117-CCA 2.44, 1081 HV, Amsterdam, The Netherlands

    Rieneke van de Ven & Tanja D. de Gruijl

  3. DCPrime B.V, De Boelelaan 1085 (W&N), 1081 HV, Amsterdam, The Netherlands

    Anneke W. Reurs, Pepijn G. J. T. B. Wijnands, Sandra van Wetering, Ada M. Kruisbeek & Rik J. Scheper

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  1. Rieneke van de Ven
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  2. Anneke W. Reurs
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  9. Tanja D. de Gruijl
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Correspondence to Tanja D. de Gruijl.

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van de Ven, R., Reurs, A.W., Wijnands, P.G.J.T.B. et al. Exposure of CD34+ precursors to cytostatic anthraquinone-derivatives induces rapid dendritic cell differentiation: implications for cancer immunotherapy. Cancer Immunol Immunother 61, 181–191 (2012). https://doi.org/10.1007/s00262-011-1039-x

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  • DOI: https://doi.org/10.1007/s00262-011-1039-x

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