Int J Cancer. 2013 Aug 3. doi: 10.1002/ijc.28413. [Epub ahead of print]

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

Belmont L, Rabbe N, Antoine M, Cathelin D, Guignabert C, Kurie J, Cadranel J, Wislez M.

Service de Pneumologie, AP-HP, Hôpital Tenon, Paris, France; Equipe de Recherche 2, GRC UPMC-04,, Université Paris 6 Pierre et Marie Curie, Service de Pneumologie, Hôpital Tenon, Paris, France.

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-rasLA1 ), with and without TLR9 inactivation (K-rasLA1 TLR9-/- and K-rasLA1 TLR9+/+ , respectively). TLR9 was functionally expressed only in mononuclear cells of K-rasLA1 TLR9+/+ mice. These mice had significantly worse survival and a higher tumor burden than K-rasLA1 TLR9-/- 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-rasLA1 TLR9+/+ mice were characterized by an angiogenic phenotype with higher concentrations of VEGF and higher microvessel density than from K-rasLA1 TLR9-/- mice. LKR13 cells, an ADC cell line-derived from K-rasLA1 mice, was subcutaneously injected into TLR9-/- and TLR9+/+ mice. Syngeneic tumors regressed in TLR9-/- but not in TLR9+/+ mice. PBMCs 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. © 2013 Wiley Periodicals, Inc.

KEYWORDS: TLR9 activation, angiogenesis, non-small-cell lung cancer, prognosis

PMID:23913633