Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance

Abstract

Compelling evidence suggests that inflammation, cell survival, and cancer are linked, with a central role played by NF-κB. Recent studies implicate some TLRs in tumor development based on their ability to facilitate tumor growth; however, to our knowledge, involvement of neither TLR7 nor TLR78 has yet been demonstrated. Here we have demonstrated expression of TLR7 and TLR8, the natural receptors for single-stranded RNA, by tumor cells in human lung cancer in situ and in human lung tumor cell lines. Stimulation with TLR7 or TLR8 agonists led to activated NF-κB, upregulated expression of the antiapoptotic protein Bcl-2, increased tumor cell survival, and chemoresistance. Transcriptional analysis performed on human primary lung tumor cells and TLR7-or TLR8-stimulated human lung tumor cell lines revealed a gene expression signature suggestive of chronic stimulation of tumor cells by TLR ligands in situ. Together, these data emphasize that TLR signaling can directly favor tumor development and further suggest that researchers developing anticancer immunotherapy using TLR7 or TLR8 agonists as adjuvants should take into account the expression of these TLRs in lung tumor cells.

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

“…Previous studies have reported pro-tumorigenic effects for different TLRs, such as TLR2 14–18 , TLR4 19–23 , TLR5 24 , TLR7 10,11,25 and TLR9 26–30 . In prostate and breast cancer, the stimulation of TLR9 induced an over-expression of matrix metalloproteinase 13 as well as an increase of cell invasion 31,32 .…”

“…However, in recent years, TLR7 expression by tumor cells has been associated with a pro-tumoral effect in pancreatic adenocarcinoma 25 and in NSCLC 10,11 . We found that stimulation of TLR7 expressed by adenocarcinoma cells modulated the immune infiltrate, leading to a significant expansion in MDSCs, associated with an increased secretion of CCL2 and GM-CSF in the tumor microenvironment.…”

“…We have previously demonstrated that TLR7, a single stranded RNA receptor that is usually expressed in endosomes of immune cells including plasmacytoid and conventional dendritic cells (pDCs and cDCs), macrophages and B lymphocytes 8,9 , is expressed by malignant cells from NSCLC patients 10 . 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.…”

Cancer pulmonaire

“…Nous avons étudié par immunohistochimie l'expression de TLR7 et TLR8 sur des coupes de tumeurs provenant de patients opérés de carcinomes pulmonaires non à petites cellules (NSCLC, non-small cell lung carcinoma) [9]. Sur une petite cohorte de 13 patients, nous avons montré que TLR7 est exprimé chez 9 patients, et TLR8 chez les 13 patients, avec des pourcentages d'expression variables allant de moins de 10 % à 100 % de cellules tumorales exprimant TLR7 et/ou TLR8.…”

“…Cette activation est dite atypique car IB est phosphorylé 30 min après la stimulation sans être dégradé. La stimulation des cellules tumorales pulmonaires par les ligands de TLR7 ou de TLR8 induit une augmentation de la survie des cellules, en accord avec une augmentation de l'expression de la protéine anti-apoptotique Bcl-2 [9,10].…”