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

Abstract

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.

Oncostatin M treatment increases the responsiveness toward cisplatin‑based chemoradiotherapy in cervical cancer cells in a STAT3‑dependent manner

“…One immunotherapeutic strategy might be usage of the synthetic viral dsRNA homolog polyinosinic:polycytidylic acid (PolyIC) that can stimulate necroptosis in cervical cancer cells expressing the kinase RIPK3 (34,35). Notably, this leads to enhanced interleukin-12 production of dendritic cells (34).…”

Stromal Fibroblasts Induce CCL20 through IL6/C/EBPβ to Support the Recruitment of Th17 Cells during Cervical Cancer Progression

“…CCL20-staining intensity was classified using the immunoreactive score (IRS; Supplementary Table S1; refs. 25,26). Biopsies were evaluated as negative (IRS 0-2) or positive (IRS 3-12; 3-4 ¼ weak, 6-8 ¼ moderate, and 9-12 ¼ strong expression).…”

STAT3/IRF1 Pathway Activation Sensitizes Cervical Cancer Cells to Chemotherapeutic Drugs

“…Bohle). Staining of 5-mm sections with Abs listed in Supplementary Table S2 was performed as described previously (10,20) and classified using the Immunoreactive Score (IRS) according to Remmele and Stegner (21). Biopsies were evaluated with standardized settings with a DMI 6000B microscope (Leica) and Microsoft Image Composite Editor program.…”

“…The total amount of DNA was adjusted to 1 mg with empty pCMV-Flag2 vector. Six or 10 pmol of indicated siRNAs (ON-TARGETplus Non-targeting siRNA #2, ON-TARGETplus siRNA #8 for human STAT3, siRNA #6 for IRF1, all from Thermo Scientific) were transfected with Lipofectamine RNAiMax (Invitrogen) as described previously (20).…”