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

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

doi:10.1158/0008-5472.can-07-5839

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.

Highlights

With the molecular identification of tumor antigens recognized by the human immune system, several cancer vaccine strategies targeting these antigens have been attempted [1,2,3,4]
Little enhancement of specific CD8+ T-cell induction was found in mice immunized with plasmids encoding mERK2 coadministered with mouse GITR ligand (GITRL) at secondary immunization
PC61 administration showed no added enhancement of CTL epitope 9m-specific CD8+ T-cell induction over that induced by CTL epitope 9m coadministered with GITRL, whereas 9m-specific T-cell induction by immunization with a CTL epitope 9m alone was markedly augmented with depletion of CD25+ cells (Fig. 2C)

Summary

Introduction

With the molecular identification of tumor antigens recognized by the human immune system, several cancer vaccine strategies targeting these antigens have been attempted [1,2,3,4]. Induction/ activation of CD4+CD25+ Tregs by immunization with self-antigens augments the number of pulmonary metastases following injection of transplantable tumor cells and enhances the development of chemically induced primary tumors [13,14,15]. CD4+CD25+ Tregs control the antigen-specific T-cell induction in both spontaneous and vaccine-induced T-cell responses [18,19,20]. For this reason, it is becoming an important priority to find new effective adjuvant formulations, vectors, or vaccination strategies for controlling Tregs in the cancer vaccine field

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Results

Conclusion