Universität zu Köln

Pahne-Zeppenfeld, Jennifer, Schroeer, Nadine, Walch-Rueckheim, Barbara, Oldak, Monika ORCID: 0000-0002-4216-9141, Gorter, Arko, Hegde, Subramanya and Smola, Sigrun (2014). Cervical cancer cell-derived interleukin-6 impairs CCR7-dependent migration of MMP-9-expressing dendritic cells. Int. J. Cancer, 134 (9). S. 2061 - 2074. HOBOKEN: WILEY. ISSN 1097-0215

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Abstract

Cervical carcinogenesis is a consequence of persistent infection with high-risk human papillomaviruses (HPVs). Recent studies indicate that HPV-transformed cells actively instruct their microenvironment to promote carcinogenesis. Here, we demonstrate that cervical cancer cells activate monocytes to produce their own CCL2 for further monocyte recruitment and reprogram their function during differentiation and maturation to dendritic cells (DCs). Our data show that cervical cancer cells suppress the induction of the chemokine receptor CCR7 in phenotypically mature DCs and impair their migration toward a lymph node homing chemokine, required to initiate adaptive immune responses. We confirmed the presence of CD83(+)CCR7(low) DCs in cancer biopsies. The second factor essential for DC migration, matrix-metalloproteinase MMP-9, which also has vasculogenic and protumorigenic properties, is not suppressed but upregulated in immature as well as mature DCs. We identified interleukin-6 (IL-6) as a crucial cervical cancer cell-derived mediator and nuclear factor kappaB (NF-kappa B) as the central signaling pathway targeted in DCs. Anti-IL-6 antibodies reverted not only NF-kappa B inhibition and restored CCR7-dependent migration but also blocked MMP-9 induction. This is the first report demonstrating the dissociation of CCR7 and MMP-9 expression in phenotypically mature CD83(+) DCs by cancer cells. Our results show that cervical cancer cells actively shape the local microenvironment. They induce the accumulation of myeloid cells and skew their function from immune activation to local production of protumorigenic MMP-9. Neutralizing anti-IL-6 antibodies can counteract this functional dysbalance and should therefore be considered for adjuvant cervical cancer therapy.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pahne-Zeppenfeld, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeer, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Walch-Rueckheim, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Oldak, Monika UNSPECIFIED orcid.org/0000-0002-4216-9141 UNSPECIFIED Gorter, Arko UNSPECIFIED UNSPECIFIED UNSPECIFIED Hegde, Subramanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Smola, Sigrun UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-440052
DOI:	10.1002/ijc.28549
Journal or Publication Title:	Int. J. Cancer
Volume:	134
Number:	9
Page Range:	S. 2061 - 2074
Date:	2014
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1097-0215
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN-PAPILLOMAVIRUS TYPE-16; NF-KAPPA-B; ANTI-IL-6 MONOCLONAL-ANTIBODY; CD8 T-CELLS; HLA CLASS-I; LANGERHANS CELLS; CARCINOMA CELLS; RECEPTOR EXPRESSION; STAT3 ACTIVATION; LYMPHOID ORGANS Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44005