TLR7 agonists are currently under investigations for their ability to enhance anti-tumor immune responses. However, in some tumor models, these agonists can also stimulate tumor cells, which express high levels of TLR7. In Non-Small-Cell Lung Carcinoma (NSCLC), we have demonstrated that high expression of TLR7 conferred poor clinical outcome and was strongly associated with resistance to chemotherapy. This protumorigenic effect of TLR7 has been validated in murine models in which the injection of TLR7 agonists in NOD/SCID mice, in C57BL/6 wild-type or in TLR7-deficient mice grafted with lung adenocarcinoma tumor cells led to increased tumor progression and chemotherapeutic resistance. TLR7 stimulation resulted in a significant increase of Myeloid-Derived Suppressor Cells (MDSC) in the tumor microenvironment. Depletion experiments of MDSC indicated that these cells appeared to be responsible to the in vivo pro-tumoral effect induced upon TLR7 stimulation. Finally, we have demonstrated that the pro-tumoral effect of TLR7 stimulation, mediated by the MDSC recruitment, was independent of stimulation of TLR7 of immune cells.
Our results reveal the mechanism by which TLR7 stimulation induce the pro-tumoral effect in mice, and open the way to the development of novel cancer therapeutics including TLR7 inhibitors, for NSCLC patients.
Citation Format: Marion Dajon, Kristina Iribarren, Isabelle Cremer. Protumoral effects of TLR7 in lung tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A124.