TLR ligands in the local treatment of established intracerebral murine gliomas
| Autor: | Erik Bennink, Roger P.M. Sutmuller, Johan W. Molling, Gosse J. Adema, Stefan Nierkens, Liza W.J. Toonen, Oliver Grauer |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
CD4-Positive T-Lymphocytes
Immunology Enzyme-Linked Immunosorbent Assay CD8-Positive T-Lymphocytes Ligands Mice Lymphocytes Tumor-Infiltrating Adjuvants Immunologic Immune Regulation [NCMLS 2] Translational research [ONCOL 3] In vivo Glioma MHC class I medicine Immunology and Allergy Animals Mice Knockout biology Brain Neoplasms Reverse Transcriptase Polymerase Chain Reaction Toll-Like Receptors FOXP3 hemic and immune systems medicine.disease Flow Cytometry In vitro Pathogenesis and modulation of inflammation [N4i 1] Mice Inbred C57BL TLR2 Oligodeoxyribonucleotides biology.protein TLR4 Cancer research Female Immunotherapy CD8 Immunity infection and tissue repair [NCMLS 1] |
| Zdroj: | Journal of Immunology, 181, 6720-9 Journal of Immunology, 181, 10, pp. 6720-9 |
| ISSN: | 0022-1767 |
| Popis: | Contains fulltext : 70899.pdf (Publisher’s version ) (Closed access) Local TLR stimulation is an attractive approach to induce antitumor immunity. In this study, we compared various TLR ligands for their ability to affect murine GL261 cells in vitro and to eradicate established intracerebral murine gliomas in vivo. Our data show that GL261 cells express TLR2, TLR3, and TLR4 and respond to the corresponding TLR ligands with increasing MHC class I expression and inducing IL-6 secretion in vitro, while TLR5, TLR7, and TLR9 are essentially absent. Remarkably, CpG-oligonucleotides (CpG-ODN, TLR9) appeared to inhibit GL261 cell proliferation in a cell-type specific, but CpG-motif and TLR9-independent manner. A single intratumoral injection of CpG-ODN most effectively inhibited glioma growth in vivo and cured 80% of glioma-bearing C57BL/6 mice. Intratumoral injection of Pam3Cys-SK4 (TLR1/2) or R848 (TLR7) also produced a significant survival benefit, whereas poly(I:C) (TLR3) or purified LPS (TLR4) stimulation alone was not effective. Additional studies using TLR9(+/+) wild-type and TLR9(-/-) knockout mice revealed that the efficacy of local CpG-ODN treatment in vivo required TLR9 expression on nontumor cells. Additional experiments demonstrated increased frequencies of tumor-infiltrating IFN-gamma producing CD4(+) and CD8(+) effector T cells and a marked increase in the ratio of CD4(+) effector T cells to CD4(+)FoxP3(+) regulatory T cells upon CpG-ODN treatment. Surviving CpG-ODN treated mice were also protected from a subsequent tumor challenge without further addition of CpG-ODN. In summary, this study underlines the potency of local TLR treatment in antiglioma therapy and demonstrates that local CpG-ODN treatment most effectively restores antitumor immunity in a therapeutic murine glioma model. |
| Databáze: | OpenAIRE |
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