Innate immune signaling through differential RIPK1 expression promote tumor progression in head and neck squamous
Kevin D McCormick1, Arundhati Ghosh1, Sumita Trivedi2
1Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Cancer Virology Program and.
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 proapoptotic 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 prosurvival NF-κB in response to p(I):p(C) resulting in an enhanced apoptotic response. Here, we show that transcriptional downregulation 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 protumorigenic 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 double stranded RNA to target metastatic tumor cells.
Insights
Metastatic head and neck cancer cells show reduced receptor-interacting serine/threonine-protein kinase 1 (RIPK1). This loss enhances apoptosis via toll-like receptor 3 (TLR3) signaling, offering new immunotherapy targets for metastatic tumors.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) requires novel treatments, including immunotherapy.
- Synthetic double-stranded RNAs activate toll-like receptor 3 (TLR3), acting as adjuvants in cancer immunotherapy by inducing apoptosis.
- Understanding TLR3-mediated apoptosis and its role in metastasis is crucial for improving HNSCC treatment.
Purpose of the Study:
- To investigate the mechanism of TLR3-mediated apoptosis in metastatic HNSCC cells.
- To determine the role of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in TLR3 signaling and apoptosis in HNSCC.
- To explore the correlation between RIPK1 expression and metastatic disease in HNSCC patients.
Main Methods:
- Comparison of primary and metastatic HNSCC cells regarding NF-κB activation in response to p(I):p(C).
- Analysis of RIPK1 expression levels in metastatic HNSCC cells and its impact on TLR3 signaling.
- Correlation analysis of RIPK1 loss with metastatic HNSCC in patient cohorts.
- Investigation of RIPK1 promoter methylation as a potential regulatory mechanism.
Main Results:
- Metastatic HNSCC cells exhibit reduced NF-κB activation and enhanced apoptosis upon TLR3 stimulation compared to primary cells.
- Transcriptional downregulation of RIPK1 in metastatic HNSCC cells leads to impaired TLR3-mediated NF-κB signaling and increased apoptosis.
- Loss of RIPK1 expression significantly correlates with metastatic HNSCC in patients.
- Reduced RIPK1 expression is associated with enhanced protumorigenic properties, including cell migration, and may be mediated by promoter hypermethylation.
Conclusions:
- A novel mechanism involving RIPK1 downregulation in metastatic HNSCC cells dictates TLR3-mediated apoptosis.
- RIPK1 loss impairs NF-κB survival signaling, promoting apoptosis in metastatic cancer cells.
- RIPK1 downregulation represents a potential therapeutic vulnerability and biomarker for metastatic HNSCC, suggesting opportunities for double-stranded RNA-based therapies.
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