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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901436v1 183/7/4371    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Chiron, D. Articles by Jego, G. PubMed PubMed Citation Articles by Chiron, D. Articles by Jego, G. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Breast Cancer Multiple Myeloma

Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis¹

David Chiron^2,*,, Catherine Pellat-Deceunynck^*,, Mike Maillasson^*,,, Régis Bataille^*, and Gaëtan Jego^*,

^* INSERM, Unité 892, Nantes, France; Université de Nantes, Unité Mixte de Recherche S892, Nantes, France; and Plateforme Interactome et Puces à Protéines Ouest Genopole, Nantes, France

Hypomethylated CpG oligodeoxynucleotides (CpG ODNs) target TLR9 expressed by immune cells and are currently being evaluated as adjuvants in clinical trials. However, TLR signaling can promote some tumor growth and immune evasion, such as in multiple myeloma (MM). Therefore, deciphering the effects of CpG ODNs on cancer cells will help in preventing these adverse effects and in designing future clinical trials. TLR activation induces multiple signaling pathways, notably NF-B that has been involved in the resistance to TRAIL. Thus, we wondered if CpG ODNs could modulate TRAIL-induced apoptosis in different models of tumors. Here, we show that TLR9⁺ (NCI-H929, NAN6, KMM1) and TLR9^– MM cells (MM1S) were protected by CpG ODNs against recombinant TRAIL-induced apoptosis. By using two fully human, agonist mAbs directed against TRAIL receptors DR4 and DR5 (mapatumumab and lexatumumab, respectively), we show that the protection was restricted to DR5-induced apoptosis. Similar results were observed for two colon cancer (C45 and Colo205) and two breast cancer cell lines (HCC1569 and Cal51). The protection of CpG ODNs was mediated by its nuclease-resistant phosphorothioate backbone independent of TLR9. We next demonstrated by surface plasmon resonance that phosphorothioate-modified CpG ODNs directly bound to either TRAIL or lexatumumab and then decreased their binding to DR5. Finally, NK cell lysis of a DR5-sensitive MM cell line (NCI-H929) through TRAIL was partially inhibited by phosphorothioate-modified CpG ODNs. In conclusion, our results suggest that the phosphorothioate modification of CpG ODNs could dampen the clinical efficacy of CpG ODN-based adjuvants by altering TRAIL/TRAIL receptor interaction.

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 study was supported by grants from La Ligue Contre le Cancer (Équipe Labélisée 2008).

² Address correspondence and reprint requests to Dr. David Chiron, Institut de Recherche Thérapeutique de l’Université de Nantes, Institut National de la Santé et de la Recherche Médicale, Unité 892, Centre de Recherches en Cancérologie Nantes Angers, 8, Quai Moncousu, BP 70721, 44007 Nantes Cedex 01, France. E-mail address: david.chiron{at}etu.univ-nantes.fr

³ Abbreviations used in this paper: CpG ODN, CpG oligodeoxynucleotide; HMCL, human myeloma cell line; MM, multiple myeloma; SPR, surface plasmon resonance.

⁴ The online version of this article contains supplemental material.