TLR7 Promotes Tumor Progression, Chemotherapy Resistance, and Poor Clinical Outcomes in Non–Small Cell Lung Cancer

Abstract

Toll-like receptors (TLR) recognize pathogen molecules and danger-associated signals that stimulate inflammatory processes. TLRs have been studied mainly in antigen-presenting cells, where they exert important immune regulatory functions, but they are also expressed by epithelial tumor cells, where they have been implicated in tumor progression. In this study, we demonstrate that the injection of TLR7 agonist in NOD/SCID mice, in C57BL/6 wild-type, and TLR7-deficient mice grafted with lung adenocarcinoma tumor cells leads to increased tumor progression and chemotherapeutic resistance. In patients with non-small cell lung cancer, expression analyses revealed that high TLR7 expression was strongly associated with resistance to neoadjuvant chemotherapy and poor clinical outcomes. Our findings delineate a crucial role for TLR7 in lung cancer physiopathology. Cancer Res; 74(18); 5008-18. Ó2014 AACR.

Toll like receptor 7 expressed by malignant cells promotes tumor progression and metastasis through the recruitment of myeloid derived suppressor cells

“…Bacterial lipopolysaccharide (LPS), an agonist of TLR4, failed to affect tumor growth (Figure 1A), while CpG, an agonist of TLR9, actually inhibited tumor growth (Figure 1B). On the contrary, intratumoral injection of the TLR7 agonist CL264 induced a pro-tumorigenic effect (Figure 1C), in accordance to our previous observations 11 .

10.1080/2162402X.2018.1505174-F0001Figure 1.Pro- or anti-tumoral effects of different TLRs stimulation.Left panel: TLR4 (A), TLR9 (B) and TLR7 (C) expression by LLC-luc cells and TLR7 expression by LLC-luc cells deficient for TLR7 (obtained by CRISPR/Cas9 technology) (D). Control isotype is shown in blue and stained cells in orange.Right panel: Tumor progression in WT C57Bl/6 mice grafted with LLC-luc cells, after LPS (A) or CpG injection (B).

…”

“…Expression of TLR7 was also validated by quantitative PCR (data not shown). We have previously demonstrated that intratumoral injection of TLR7 agonist results in increased tumor progression in immunocompetent as well as in immunodeficient mice 11 . However, the precise mechanisms involved in such pro-tumorigenic effects are elusive.…”

“…We first determined the prognostic value of TLR7 on a cohort of 154 adenocarcinoma patients (sup Table 1), the malignant cells of whom displayed TLR7 either at a rather low level (< 5%) or were almost completely positive (> 82%, cut off determined in 11 ). We found that high TLR7 expression by tumor cells was associated with poor clinical outcome compared to low TLR7 expression, with a median OS of 45 months, compared to 90 months, respectively (Figure 7A).…”

“…Optimal cutoff of 82% was previously determined 11 . Patients are divided into TLR7 hi (> 82% expression of TLR7) and TLR7 low group (< 5% TLR7 expression).…”

“…High expression by cancer cells was associated with poor prognosis, both in early stages that were treated with surgery alone and more advanced stages treated by neo-adjuvant chemotherapy. Moreover, in a mouse model of lung cancer, TLR7 stimulation favored tumor growth 11 . The present study has been designed to decipher the mechanisms involved in the pro-tumorigenic and possible pro-metastatic effects of TLR7 stimulation.…”