title: Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR.
abstract: 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.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Wang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Jiang
authors.forename: Camie
authors.initials: C
authors.lastname: Chan
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Gorski
authors.forename: Erin
authors.initials: E
authors.lastname: McCadden
authors.forename: David
authors.initials: D
authors.lastname: Kardian
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Whartenby
mesh_terms: 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
chemical_list: 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