Abstract

Head and neck squamous cell carcinoma (HNSCC) is a devastating disease for which new treatments, such as immunotherapy are needed. Synthetic double-stranded RNAs, which activate Toll-like receptor 3 (TLR3), have been used as potent adjuvants in cancer immunotherapy by triggering a pro-apoptotic response in cancer cells. A better understanding of the mechanism of TLR3-mediated apoptosis and its potential involvement in controlling tumor metastasis could lead to improvements in current treatment. Using paired, autologous primary and metastatic HNSCC cells we previously showed that metastatic, but not primary tumor-derived cells, were unable to activate pro-survival NF-κB in response to p(I):p(C) resulting in an enhanced apoptotic response. Here we show that transcriptional down-regulation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in metastatic HNSCC cells causes a loss of TLR3-mediated NF-κB signaling, resulting in enhanced apoptosis. Loss of RIPK1 strongly correlates with metastatic disease in a cohort of HNSCC patients. This downregulation of RIPK1 is possibly mediated by enhanced methylation of the RIPK1 promoter in tumor cells and enhances pro-tumorigenic properties such as cell migration. The results described here establish a novel mechanism of TLR3 mediated apoptosis in metastatic cells and may create new opportunities for using dsRNA to target metastatic tumor cells.

By Kevin Dylan McCormick, Arundhati Ghoshm, Sumita Trivedi, Lin Wang, Carolyn B. Coyne, Robert L. Ferris, Saumendra N. Sarkar