title: Induction of the glucocorticoid-induced leucine zipper gene limits the efficacy of dendritic cell vaccines.
abstract: Dendritic cell (DC) vaccines have shown great promise in generating antitumor immune responses but have generally fallen short of producing durable cures. Determining mechanisms by which these vaccines fail will provide one strategy toward improving their success. Several manipulations of DCs have improved their migration and longevity, but the immune inhibitory environment surrounding tumors provides a powerful suppressive influence. To determine the mechanisms by which DCs at the site of the tumor convert to a suppressive phenotype, we evaluated pathways in DCs that become expressed at the tumor site. Our results revealed that tumors lead to induction of the glucocorticoid-induced leucine zipper (GILZ) gene in DCs, and that this gene is critical for the development of tumor-induced tolerance of both DCs and T cells. Previous data suggested that GILZ is a pivotal gene in the balance between activation and tolerance of DCs. Our new data show that GILZ is highly upregulated in DCs in the tumor microenvironment in vivo and that blockade of this gene in DC vaccines significantly improves long-term survival. These results suggest that GILZ may be an ideal candidate gene to target for novel immune-based tumor therapies.
authors.affiliation: Department of Neurology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lebson
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: Q
authors.initials: Q
authors.lastname: Jiang
authors.forename: K A
authors.initials: KA
authors.lastname: Whartenby
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D019496:Cancer Vaccines; D005938:Glucocorticoids; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D003907:Dexamethasone