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Phosphorothioate-modified TLR9 ligands protect cancer cells against TRAIL-induced apoptosis

David Chiron1, Catherine Pellat-Deceunynck, Mike Maillasson

  • 1Institut de Recherche Thérapeutique de l'Université de Nantes, Institut National de la Santé et dela Recherche Médicale, Unité 892, Centre de Recherches en Cancérologie Nantes Angers, 8, Quai Moncousu, BP 70721, 44007 Nantes Cedex 01, France. david.chiron@etu.univ-nantes.fr

Journal of Immunology (Baltimore, Md. : 1950)
|September 8, 2009
PubMed

Insights

CpG oligodeoxynucleotides (CpG ODNs) protect cancer cells from TRAIL-induced apoptosis by binding to TRAIL receptors, potentially reducing the efficacy of CpG ODN adjuvants in cancer therapy.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • CpG oligodeoxynucleotides (CpG ODNs) activate Toll-like receptor 9 (TLR9) on immune cells, acting as adjuvants in clinical trials.
  • TLR signaling can paradoxically promote tumor growth and immune evasion, necessitating investigation into CpG ODN effects on cancer cells.
  • Understanding CpG ODN interactions with cancer cells is crucial for optimizing cancer therapies and clinical trial design.

Purpose of the Study:

  • To investigate whether CpG ODNs modulate TRAIL-induced apoptosis in various cancer cell models.
  • To determine the specific TRAIL receptor (DR4 or DR5) involved in CpG ODN-mediated protection.
  • To elucidate the mechanism by which CpG ODNs confer protection against TRAIL-induced apoptosis.

Main Methods:

  • Treatment of multiple myeloma, colon, and breast cancer cell lines with CpG ODNs and recombinant TRAIL or TRAIL receptor agonist antibodies (mapatumumab, lexatumumab).
  • Assessment of apoptosis induction and NK cell-mediated lysis.
  • Surface plasmon resonance to analyze direct binding interactions between CpG ODNs, TRAIL, lexatumumab, and DR5.

Main Results:

  • CpG ODNs protected both TLR9-positive and TLR9-negative cancer cells from TRAIL-induced apoptosis.
  • Protection was specifically mediated through the DR5 receptor, not DR4.
  • The phosphorothioate backbone of CpG ODNs was responsible for the protective effect, independent of TLR9 activation.
  • CpG ODNs directly bound to TRAIL and lexatumumab, inhibiting their interaction with DR5.
  • CpG ODNs partially inhibited NK cell-mediated lysis of cancer cells via TRAIL.

Conclusions:

  • CpG ODNs, via their phosphorothioate backbone, can inhibit TRAIL/TRAIL receptor interactions, specifically with DR5.
  • This interaction leads to protection of cancer cells from TRAIL-induced apoptosis and reduced NK cell-mediated cytotoxicity.
  • The findings suggest that the phosphorothioate modification in CpG ODN-based adjuvants may dampen their clinical efficacy by interfering with crucial anti-cancer mechanisms like the TRAIL pathway.

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