Submitted August 28, 2008
Accepted December 24, 2008
Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR
Tianhong Wang, Qiong Jiang, Camie Chan, Kevin S. Gorski, Erin McCadden, David Kardian, Drew Pardoll, and Katharine A. Whartenby*
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
SA Biosciences, Frederick, MD, United States
Department of Cell Biology and Human Anatomy, School of Medicine, University of California, Davis, CA, United States
Amgen, Inc., Thousand Oaks, CA, United States
* Corresponding author; email: whartenby{at}jhmi.edu.
Activation of dendritic cells (DCs) leads to cell maturation, which is accompanied by a regulated pattern of gene expression changes. Two significant and contradictory consequences of DC activation are that while activation is necessary for maximal T cell stimulation, it also leads to the initiation of gene expression that results ultimately in cell death. We have identified a gene, MINOR (mitogen inducible nuclear orphan receptor), that becomes highly upregulated upon activation and whose expression leads to the initiation of apoptosis in mature DCs. MINOR is a member of the Nur77 family of nuclear orphan receptors, which includes Nur77 and Nurr1. While Nur77 and Nurr1 are expressed in macrophages and DCs, our data indicate that their expression does not change upon DC maturation or activation. We thus tested the hypothesis that induction of MINOR led to an activation-induced cell death in DCs and that its inhibition would increase the lifespan of DCs and improve their vaccine efficacy. In order to block natural expression of MINOR by DCs, we have generated a lentiviral vector that expresses a small interfering RNA. Our results indicate that siRNA-mediated blockade of MINOR expression dramatically decreases apoptosis in DCs and suggest that this approach may be a novel means to improve the potency of ex vivo generated DC vaccines.
