Toll-like receptor 3 (TLR3) mediates innate immune responses by sensing viral dsRNA, but also induces apoptosis selectively in
cancer cells. Our analysis by immunohistochemistry revealed that TLR3 is frequently overexpressed in 130
non-small cell lung cancer (NSCLC) patients' samples compared with normal bronchial epithelium (P < 0.0001, Mann-Whitney test), supporting the therapeutic potential of TLR3
ligand for this type of
cancer. However, a proportion of TLR3-expressing
cancer cell lines, including NSCLC, remain resistant to TLR3-mediated apoptosis, and the underlying mechanism of resistance remains unclear. We here investigated the molecular basis conferring resistance to non-transformed vs. transformed cells against TLR3-mediated cell death. In non-transformed epithelial cells cellular FLICE-like inhibitory
protein (c-FLIP) and cellular Inhibitor of APoptosis (cIAPs)
ubiquitin ligases exerted an efficient double brake on apoptosis signaling. In contrast, releasing only one of these two brakes was sufficient to overcome the resistance of 8/8
cancer cell lines tested. Remarkably, the release of the c-FLIP, but not cIAPs, brake only results in the sensitization of all human
cancer cells to TLR3-mediated apoptosis. Taking advantage of the difference between transformed and non-transformed cells, we developed a rational strategy by combining the chemotherapeutic agent
paclitaxel, which decreases c-FLIP expression, with TLR3
ligand. This combination was highly synergistic for triggering apoptosis in
cancer cells but not in non-transformed cells. In vivo, the combination of
paclitaxel with dsRNA delayed
tumor growth and prolonged survival in a mouse xenograft lung
tumor model. In conclusion, combining the release of the c-FLIP brake with TLR3
ligand synergizes to selectively kill
cancer cells, and could represent an efficient and safe
therapy against TLR3-expressing
cancers such as NSCLC.