title: Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling.
abstract: We previously found that a Salmonella typhimurium vector engineered to secrete soluble tumor antigen induces CD4(+) T cells resistant to CD4(+)CD25(+) regulatory T cells (Treg) and that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) signal is involved in the development of this resistance. In this study, we address the potential of incorporating GITR ligand (GITRL) as a way to augment the immunogenicity of cancer vaccines. BALB/c mice were immunized by gene gun with plasmids encoding the mutated extracellular signal-regulated kinase 2 (mERK) with or without plasmids encoding mouse GITRL. Coadministration with GITRL during primary and secondary immunization enhanced the induction of mERK-specific CD8(+) T cells. Antibody depletion and minigene analysis suggested that GITRL directly activated CTL epitope-specific CD8(+) T cells independently of CD4(+) T cells. Immunization with plasmids encoding a CTL epitope and GITRL resulted in strong tumor inhibition in a CD8(+) T cell-dependent manner. Furthermore, CTL epitope-specific CD8(+) T cells induced by immunization with plasmids encoding CTL epitope coadministered with GITRL were refractory to suppression by CD4(+)CD25(+) Tregs compared with CD8(+) T cells induced without GITR signaling. We propose that coadministration of GITR signaling agents with tumor antigens constitutes a promising novel strategy for cancer vaccine development.
authors.affiliation: Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan. nisihiro@clin.medic.mie-u.ac.jp
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Takuma
authors.initials: T
authors.lastname: Kato
authors.forename: Michiko
authors.initials: M
authors.lastname: Hirayama
authors.forename: Yuki
authors.initials: Y
authors.lastname: Orito
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.forename: Naozumi
authors.initials: N
authors.lastname: Harada
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D005260:Female; D005822:Genetic Vectors; D005938:Glucocorticoids / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000939:Epitopes; D005938:Glucocorticoids; D053645:Interleukin-2 Receptor alpha Subunit; D048069:Tumor Necrosis Factors; D019950:Mitogen-Activated Protein Kinase 1