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

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]