Dajon and Iribarren et al. used a murine lung adenocarcinoma model to show that stimulation of TLR7 on malignant, but not stromal, cells leads to secretion of CCL2 and GM-CSF in the TME and to recruitment of MDSCs, which promotes accelerated tumor growth and metastasis. In adenocarcinoma patients, high TLR7 expression on tumor cells was an independent prognostic marker for poor clinical outcome, and was associated with a gene expression profile of metastasis (overexpression of ICAM-1, KRT-7, KRT-19, NME1, SDC4, and TP53) and a phenotype of epithelial-mesenchymal transition (increased vimentin and decreased E-cadherin).
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.
Author Info: (a)Institut National de la Santé et de la Recherche Medicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris, France.
(b)Sorbonne Université, Paris, France.
(c)Univer
Author Info: (a)Institut National de la Santé et de la Recherche Medicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris, France.
(b)Sorbonne Université, Paris, France.
(c)Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
(d)Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.
(e)Departments of Pathology and Thoracic Surgery, Hospital Cochin AP-HP, Paris, France.
(f)Unité de de Biologie Cellulaire des Lymphocytes INSERM U1221, Institut Pasteur, Paris, France.
(g)Cell Biology and Metabolomics Platforms, Villejuif, France.
(h)Equipe 11 labellisee Ligue Nationale Contre le Cancer, Paris, France.
(i)Pôle de Biologie, Hopital Europeen Georges Pompidou, AP-HP, Paris, France.
(j)Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
