TY - JOUR
T1 - Expression of TLR9 in tumor-infiltrating mononuclear cells enhances angiogenesis and is associated with a worse survival in lung cancer
AU - Belmont, Laure
AU - Rabbe, Nathalie
AU - Antoine, Martine
AU - Cathelin, Dominique
AU - Guignabert, Christophe
AU - Kurie, Jonathan
AU - Cadranel, Jacques
AU - Wislez, Marie
PY - 2014/2/15
Y1 - 2014/2/15
N2 - 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.
AB - 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.
KW - TLR9 activation
KW - angiogenesis
KW - non-small-cell lung cancer
KW - prognosis
UR - http://www.scopus.com/inward/record.url?scp=84890125832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84890125832&partnerID=8YFLogxK
U2 - 10.1002/ijc.28413
DO - 10.1002/ijc.28413
M3 - Article
C2 - 23913633
AN - SCOPUS:84890125832
SN - 0020-7136
VL - 134
SP - 765
EP - 777
JO - International journal of cancer
JF - International journal of cancer
IS - 4
ER -