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Regulatory T Cell–Resistant CD8⁺ T Cells Induced by Glucocorticoid-Induced Tumor Necrosis Factor Receptor Signaling

Departments of ¹ Cancer Vaccine, ² Bioregulation, and ³ Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan; ⁴ Department of Pathology, Tokyo Medical University; ⁵ ImmunoFrontier, Inc., Tokyo, Japan; and ⁶ Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Hiroyoshi Nishikawa, Department of Cancer Vaccine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Phone: 81-59-231-5187; Fax: 81-59-231-5276; E-mail: nisihiro{at}clin.medic.mie-u.ac.jp or Hiroshi Shiku, Department of Cancer Vaccine and Immuno-Gene Therapy, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Phone: 81-59-231-5062; Fax: 81-59-231-5276; E-mail: shiku{at}clin.medic.mie-u.ac.jp.

Key Words: Regulatory T cells • CD8⁺ T cells • GITR ligand • Cancer vaccine • Mouse model

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. [Cancer Res 2008;68(14):5948–54]