Abstracts (complete list) - Wissenschaft Online

Jenny Pahne, Subramanya Hegde, Nadine Schröer, Sigrun Smola-Hess
Tumor cell-derived interleukin-6 skews myeloid dendritic
cells from an immunostimulatory to a pro-tumorigenic
phenotype
Persistent infection with human papillomaviruses can lead to cervical intraepithelial
neoplasia, which after years may further progress to cancer. Development of malignant
disease is not the direct consequence of infection but the result of a complex interplay
between the transformed cells and their microenvironment. During progression to
malignancy a pronounced shift from TH1 to TH2 cytokines is observed. As a
consequence, cytotoxic T cell responses necessary to eliminate the tumor are impaired.
Currently, the mechanism, how cervical neoplastic cells contribute to this immunological
shift is not known.
Here we show that supernatants of cervical carcinoma cells suppress up-regulation of
CCR7 and production of interleukin-12 (IL-12) in myeloid dendritic cells, which is
important for mounting a TH1 response. Signalling pathways regulating CCR7 and IL-12
expression were investigated. Supernatants of neoplastic cells strongly inhibited nuclear
factor-kappaB (NF-kappaB) binding activity in dendritic cells, which is central to their
immunostimulatory function. Corresponding to the expression pattern in vivo, cervical
carcinoma cells did not produce IL-10 in vitro, but the pro-inflammatory cytokine IL-6.
Neutralization of IL-6 in cervical cancer cell supernatants restored IL-12 production and
NF-kappaB binding activity in dendritic cells. Of note, not all functions of dendritic cells
were suppressed by the neoplastic cells. Despite inhibition of NF-kappaB binding
activity, tumor cell-derived IL-6 up-regulated the pro-angiogenic and pro-tumorigenic
matrix-metalloproteinase MMP-9 in dendritic cells.
In summary, our data demonstrate that tumor cell-derived IL-6 skews dendritic cells
from an immunostimulatory to a pro-tumorigenic phenotype.