RIPK3 expression in cervical cancer cells is required for PolyIC-induced necroptosis, IL-1α release, and efficient paracrine dendritic cell activation

Oncotarget. 2015 Apr 20;6(11):8635-47. doi: 10.18632/oncotarget.3249.


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.

Keywords: RIPK3; cervical cancer; dendritic cells; human papilloma virus.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Adenocarcinoma / virology
  • Apoptosis / drug effects
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology*
  • Carcinoma, Squamous Cell / virology
  • Caspase 3 / physiology
  • Dendritic Cells / immunology
  • Female
  • Gene Expression Regulation, Neoplastic
  • HMGB1 Protein / metabolism
  • HeLa Cells
  • Humans
  • Interferon Inducers / pharmacology*
  • Interleukin-12 / biosynthesis
  • Interleukin-12 / genetics
  • Interleukin-1alpha / metabolism*
  • Necrosis
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Papillomaviridae / drug effects
  • Papillomavirus Infections / immunology
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology
  • Paracrine Communication / drug effects*
  • Poly I-C / pharmacology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / biosynthesis
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology*
  • Uterine Cervical Neoplasms / immunology
  • Uterine Cervical Neoplasms / pathology*


  • HMGB1 Protein
  • HMGB1 protein, human
  • Interferon Inducers
  • Interleukin-1alpha
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Interleukin-12
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • CASP3 protein, human
  • Caspase 3
  • Poly I-C