Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR.
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, although 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 up-regulated on activation and whose expression leads to apoptosis in mature DCs. MINOR is a member of the Nur77 family of nuclear orphan receptors, which includes Nur77 and Nurr1. Although Nur77 and Nurr1 are expressed in macrophages and DCs, their expression levels do not change on DC activation. We thus tested the hypothesis that induction of MINOR would lead to an activation-induced cell death in DCs and that its inhibition would increase the lifespan of DCs and improve their vaccine efficacy. To block natural expression of MINOR by DCs, we generated a lentiviral vector that expresses a small interfering RNA. Our results indicate that 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.
Wang
Tianhong
T
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Jiang
Qiong
Q
Chan
Camie
C
Gorski
Kevin S
KS
McCadden
Erin
E
Kardian
David
D
Pardoll
Drew
D
Whartenby
Katharine A
KA
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D019672:Genes, T-Cell Receptor; D016219:Immunotherapy, Adoptive; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology*; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone