Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition

Abstract

Bortezomib (BTZ) is a potent and reversible proteasome inhibitor which has shown efficacy in the treatment of multiple myeloma. BTZ also affects NF-κB 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-κB 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 DCdependent induction of antitumor immunity.