The aryl hydrocarbon receptor antagonist StemRegenin 1 promotes human plasmacytoid and myeloid dendritic cell development from CD34+ hematopoietic progenitor cells

Soley Thordardottir, Basav N. Hangalapura, Tim Hutten, Marta Cossu, Jan Spanholtz, Nicolaas Schaap, Timothy R D J Radstake, Robbert Van Der Voort, Harry Dolstra

Research output: Contribution to journalArticle

Abstract

The superiority of dendritic cells (DCs) as antigen-presenting cells has been exploited in numerous clinical trials, where generally monocyte-derived DCs (Mo-DCs) are injected to induce immunity in patients with cancer or infectious diseases. Despite promising expansion of antigen-specific T cells, the clinical responses following vaccination have been limited, indicating that further improvements of DC vaccine potency are necessary. Pre-clinical studies suggest that vaccination with combination of primary DC subsets, such as myeloid and plasmacytoid blood DCs (mDCs and pDCs, respectively), may result in stronger clinical responses. However, it is a challenge to obtain high enough numbers of primary DCs for immunotherapy, since their frequency in blood is very low. We therefore explored the possibility to generate them from hematopoietic progenitor cells (HPCs). Here, we show that by inhibiting the aryl hydrocarbon receptor with its antagonist StemRegenin 1 (SR1), clinical-scale numbers of functional BDCA2+BDCA4+ pDCs, BDCA1+ mDCs, and BDCA3+DNGR1+ mDCs can be efficiently generated from human CD34+ HPCs. The ex vivo-generated DCs were phenotypically and functionally comparable to peripheral blood DCs. They secreted high levels of pro-inflammatory cytokines such as interferon (IFN)-α, interleukin (IL)-12, and tumor necrosis factor (TNF)-α and upregulated co-stimulatory molecules and maturation markers following stimulation with Toll-like receptor (TLR) ligands. Further, they induced potent allogeneic T-cell responses and activated antigen-experienced T cells. These findings demonstrate that SR1 can be exploited to generate high numbers of functional pDCs and mDCs from CD34 + HPCs, providing an alternative option to Mo-DCs for immunotherapy of patients with cancer or infections.

Original languageEnglish
Pages (from-to)955-967
Number of pages13
JournalStem Cells and Development
Volume23
Issue number9
DOIs
Publication statusPublished - May 1 2014

    Fingerprint

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Hematology
  • Medicine(all)

Cite this

Thordardottir, S., Hangalapura, B. N., Hutten, T., Cossu, M., Spanholtz, J., Schaap, N., Radstake, T. R. D. J., Van Der Voort, R., & Dolstra, H. (2014). The aryl hydrocarbon receptor antagonist StemRegenin 1 promotes human plasmacytoid and myeloid dendritic cell development from CD34+ hematopoietic progenitor cells. Stem Cells and Development, 23(9), 955-967. https://doi.org/10.1089/scd.2013.0521