Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling

Hiroyoshi Nishikawa, Takuma Kato, Michiko Hirayama, Yuki Orito, Eiichi Sato, Naozumi Harada, Sacha Gnjatic, Lloyd J. Old, Hiroshi Shiku

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

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.

Original languageEnglish
Pages (from-to)5948-5954
Number of pages7
JournalCancer Research
Volume68
Issue number14
DOIs
StatePublished - 15 Jul 2008
Externally publishedYes

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