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TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas¹

Oliver M. Grauer^*,, Johan W. Molling, Erik Bennink, Liza W. J. Toonen, Roger P. M. Sutmuller^2,, Stefan Nierkens and Gosse J. Adema^3,

^* Department of Neurology, University of Regensburg, Regensburg, Germany; and Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the German Research Foundation (Dr. Oliver M. Grauer, GR2089/1-1) and funds from the Dutch Cancer Society (KWF2003-2893, Prof. Gosse J. Adema), and was performed in part within the framework of project D1-101 of Top Institute Pharma. Dr. Roger P. Sutmuller was supported by a VENI grant from the Netherlands Organisation for Scientific Research (NOW grant 91656130).

² Current address: N.V. Organon, Target Discovery, Oss, The Netherlands.

³ Address correspondence and reprint requests to Prof. G. J. Adema, Tumor Immunology Laboratory, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail address: G.Adema{at}ncmls.ru.nl

⁴ Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; poly(I:C), polyinosinic-polycytidylic acid; CpG-ODN, CpG-oligonucleotide; TIL, tumor-infiltrating lymphocyte; Teff, effector T cell; BMDC, bone marrow derived dendritic cell; cLN, cervical lymph node; mLN, mesenterial lymph node.