Expression of TLR9 in tumor-infiltrating mononuclear cells enhances angiogenesis and is associated with a worse survival in lung cancer

Laure Belmont, Nathalie Rabbe, Martine Antoine, Dominique Cathelin, Christophe Guignabert, Jonathan Kurie, Jacques Cadranel, Marie Wislez

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Toll-like receptors (TLRs) play a crucial role in the innate and adaptive immune responses against microbial infection, tissue injury and cancer. Ligands of TLR9 have been developed as therapy in non-small-cell lung carcinoma (NSCLC). However, phase III clinical trials in metastatic NSCLC were negative. Our objective was to determine whether TLR9 affects tumor growth. We generated a mouse model of lung adenocarcinoma (ADC) mutated for K-ras (K-ras LA1), with and without TLR9 inactivation (K-ras LA1TLR9-/- and K-rasLA1TLR9+/+, respectively). TLR9 was functionally expressed only in mononuclear cells of K-rasLA1TLR9+/+ mice. These mice had significantly worse survival and a higher tumor burden than K-rasLA1TLR9-/- mice. Lung tumors were analyzed for 24 cytokines/growth factors using Bio-Plex multiplex bead-based assays. Factor VIII was assessed by immunochemistry. Tumors from K-rasLA1TLR9+/+ mice were characterized by an angiogenic phenotype with higher concentrations of vascular endothelial growth factor (VEGF) and higher microvessel density than from K-ras LA1TLR9-/- mice. LKR13 cells, an ADC cell line derived from K-rasLA1 mice, were subcutaneously injected into TLR9 -/- and TLR9+/+ mice. Syngeneic tumors regressed in TLR9-/- but not in TLR9+/+ mice. Peripheral blood mononuclear cells from TLR9-/- mice released less VEGF than those from TLR9+/+ mice. In 61 patients with early-stage NSCLC, TLR9 was expressed in mononuclear cells that infiltrated tumors, as assessed by immunochemistry, and contributed to worse survival. Our results suggest that TLR9 expression in mononuclear cells was associated with an angiogenic phenotype and promoted lung cancer progression. These findings may aid clinical development of TLR9 ligands to treat cancers. What's new? In the quest to bring the body's own immune defenses to bear against cancer, researchers have investigated the receptor TLR9, a toll-like receptor that initiates a cascade of immune responses. Although activating TLR9 provided a boost to chemotherapy in animal models, further trials showed no benefit over chemotherapy alone. The current study compared lung cancer in mice with and without TLR9 inactivation. The authors found that expressing TLR9 promoted angiogenesis and cancer progression, and reduced survival. Perhaps understanding how TLR9 boosts angiogenesis can help refine its development as an anti-cancer agent.

Original languageEnglish (US)
Pages (from-to)765-777
Number of pages13
JournalInternational journal of cancer
Volume134
Issue number4
DOIs
StatePublished - Feb 15 2014

Keywords

  • TLR9 activation
  • angiogenesis
  • non-small-cell lung cancer
  • prognosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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