IMR Press / JMCM / Volume 1 / Issue 1 / DOI: 10.31083/j.jmcm.2018.01.005
Open Access Research article
Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition
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1 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
2 Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam, The Netherlands
3 Onyx Pharmaceuticals/Amgen, Inc. South San Francisco, CA, U.S.A.
4 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands (Tanja D. de Gruijl)
J. Mol. Clin. Med. 2018, 1(1), 37–46;
Revised: 3 November 2017 | Accepted: 24 November 2017 | Published: 20 January 2018

Bortezomib (BTZ) is a potent and reversible proteasome inhibitor which has shown efficacy in the treatment of multiple myeloma. BTZ also affects NF-$\kappa$B activity, however, the same mechanisms through which it curtails malignant cell proliferation may also compromise antitumor immunity. As dendritic cells (DC) play a vital role in the elicitation and maintenance of antitumor immunity, we herein studied the long-term effects of BTZ on human DC development and function. The CD34$^{+}$ MUTZ-3 cell line, stably transduced with human telomerase reverse transcriptase (hTERT), was employed as a sustainable model to study human steady-state DC development and was grown in the presence of gradually increasing BTZ concentrations over a period of 4 months. The resultant BTZ-adapted cells were prospectively assessed for their ability to develop into mature Langerhans cells (LC). Long-term exposure to BTZ (>10 months) at a clinically relevant and apoptosis-inducing concentration (10 nM) provoked spontaneous differentiation in surviving precursors, evidenced by increased expression levels of CD14, TNF receptors and immunoproteasome subunits. Cytokine-dependent differentiation was also enhanced, resulting in increased numbers of mature DC with higher levels of co-stimulatory molecules and an increased capacity for T cell induction. Assessment of nuclear NF-$\kappa$B subunit levels provided evidence for a role of canonical RelB/p50 activation in the enhanced DC differentiation and maturation established through prolonged BTZ exposure. We conclude that long-term treatment with low dose BTZ is consistent with DC-dependent induction of antitumor immunity.

Poteasome inhibitor
Dendritic cell
Langerhans cells
Fig. 1.
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