RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis, IL-1α release, and efficient paracrine dendritic cell activation
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Susanne V. Schmidt1, Stefanie Seibert2, Barbara Walch-Rückheim2, Benjamin Vicinus2, Eva-Maria Kamionka2, Jennifer Pahne-Zeppenfeld1, Erich-Franz Solomayer3, Yoo-Jin Kim4, Rainer M. Bohle4, Sigrun Smola1,2
1Center for Molecular Medicine Cologne and Institute of Virology, University of Cologne, Germany
2Institute of Virology, Saarland University, Homburg/Saar, Germany
3Department of Gynecology and Obstetrics, Saarland University, Homburg/Saar, Germany
4Department of Pathology, Saarland University, Homburg/Saar, Germany
Sigrun Smola, e-mail: [email protected]
Keywords: cervical cancer, human papilloma virus, dendritic cells, RIPK3
Received: November 06, 2014 Accepted: January 28, 2015 Published: March 20, 2015
Previous studies have shown that cervical cancer cells only release low levels of pro-inflammatory cytokines owing to infection with human papillomaviruses. This results in low immunogenicity of the cancer cells. The viral dsRNA analog PolyIC has been suggested as a promising adjuvant for cervical cancer immunotherapy. However, little is known about the molecular requirements resulting in successful immune activation. Here, we demonstrate that stimulation of cervical cancer cells with PolyIC induced necroptotic cell death, which was strictly dependent on the expression of the receptor-interacting protein kinase RIPK3. Necroptotic cancer cells released interleukin-1α (IL-1α), which was required for powerful activation of dendritic cells (DC) to produce IL-12, a cytokine critical for anti-tumor responses. Again both, IL-1α release and DC activation, were strictly dependent on RIPK3 expression in the tumor cells. Of note, our in situ analyses revealed heterogeneous RIPK3 expression patterns in cervical squamous cell carcinomas and adenocarcinomas. In summary, our study identified a novel RIPK3-dependent mechanism that explains how PolyIC-treatment of cervical cancer cells leads to potent DC activation. Our findings suggest that the RIPK3 expression status in cervical cancer cells might critically influence the outcome of PolyIC-based immunotherapeutic approaches and should therefore be assessed prior to immunotherapy.
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