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

In non-small cell lung carcinoma (NSCLC), stimulation of toll-like receptor 7 (TLR7), a receptor for single stranded RNA, is linked to tumor progression and resistance to anticancer chemotherapy. However, the mechanism of this effect has been elusive. Here, using a murine model of lung adenocarcinoma, we demonstrate a key role for TLR7 expressed by malignant (rather than by stromal and immune) cells, in the recruitment of myeloid derived suppressor cells (MDSCs), induced after TLR7 stimulation, resulting in accelerated tumor growth and metastasis. In adenocarcinoma patients, high TLR7 expression on malignant cells was associated with poor clinical outcome, as well as with a gene expression signature linked to aggressiveness and metastastic dissemination with high abundance of mRNA encoding intercellular adhesion molecule 1 (ICAM-1), cytokeratins 7 and 19 (KRT-7 and 19), syndecan 4 (SDC4), and p53. In addition, lung tumors expressing high levels of TLR7 have a phenotype of epithelial mesenchymal transition with high expression of vimentin and low abundance of E-cadherin. These data reveal a crucial role for cancer cell-intrinsic TLR7 expression in lung adenocarcinoma progression.

Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword.

Toll-like receptors (TLRs) are a family of transmembrane receptors that recognize various pathogen- and damage-associated molecular pattern molecules playing an important role in inflammation by activating NF-кB. TLRs, mainly expressed by innate immune cells, are involved in inducing and regulating adaptive immune responses. However, the expression of TLRs has also been observed in many tumors, and their stimulation results in tumor progression or regression, depending on the TLR and tumor type. Here we review the role of TLRs in conferring anti- or pro-tumoral effects. The anti-tumoral effects can result from direct induction of tumor cell death and/or activation of efficient anti-tumoral immune responses, and the pro-tumoral effects may be due to inducing tumor cell survival and proliferation or by acting on suppressive or inflammatory immune cells in the tumor microenvironment.

Dual roles of TLR7 in the lung cancer microenvironment.

Toll-like receptor 7 (TLR7) agonists are under investigation for their ability to enhance antitumor immune responses. However, these agonists can also stimulate TLR7-expressing tumor cells. High TLR7 expression in the primary tumor confers poor clinical outcome and resistance to chemotherapy in lung cancer patients. This protumorigenic effect of TLR7 has been validated in murine models of lung carcinoma.