Universität zu Köln

Walch-Rueckheim, Barbara, Stroeder, Russalina, Theobald, Laura, Pahne-Zeppenfeld, Jennifer, Hegde, Subramanya, Kim, Yoo-Jin, Bohle, Rainer Maria, Juhasz-Boess, Ingolf, Solomayer, Erich-Franz and Smola, Sigrun (2019). Cervical Cancer-Instructed Stromal Fibroblasts Enhance IL23 Expression in Dendritic Cells to Support Expansion of Th17 Cells. Cancer Res., 79 (7). S. 1573 - 1587. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

Persistent infection with high-risk human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. HPV-transformed cells actively instruct their microenvironment, promoting chronic inflammation and cancer progression. We previously demonstrated that cervical cancer cells contribute to Th17 cell recruitment, a cell type with protumorigenic properties. In this study, we analyzed the expression of the Th17-promoting cytokine IL23 in the cervical cancer micromilieu and found CD83(+) mature dendritic cells (mDC) coexpressing IL23 in the stroma of cervical squamous cell carcinomas in situ. This expression of IL23 correlated with stromal Th17 cells, advanced tumor stage, lymph node metastasis, and cervical cancer recurrence. Cocultures of cervical cancer-instructed mDCs and cervical fibroblasts led to potent protumorigenic expansion of Th17 cells in vitro but failed to induce antitumor Th1 differentiation. Correspondingly, cervical cancer-instructed fibroblasts increased IL23 production in cocultured cervical cancer-instructed mDCs, which mediated subsequent Th17 cell expansion. In contrast, production of the Th1-polarizing cytokine IL12 in the cancer-instructed mDCs was strongly reduced. This differential IL23 and IL12 regulation was the consequence of an increased expression of the IL23 subunits IL23p19 and IL12p40 but decreased expression of the IL12 subunit IL12p35 in cervical cancer-instructed mDCs. Cervical cancer cell-derived IL6 directly suppressed IL12p35 in mDCs but indirectly induced IL23 expression in fibroblast-primed mDCs via CAAT/enhancer-binding protein beta (C/EBP beta)-dependent induction of IL1 beta. In summary, our study defines a mechanism by which the cervical cancer micromilieu supports IL23-mediated Th17 expansion associated with cancer progression. Significance: Cervical cancer cells differentially regulate IL23 and IL12 in DC fibroblast cocultures in an IL6/C/EBP beta/IL1 beta-dependent manner, thereby supporting the expansion of Th17 cells during cancer progression.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Walch-Rueckheim, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroeder, Russalina UNSPECIFIED UNSPECIFIED UNSPECIFIED Theobald, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Pahne-Zeppenfeld, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Hegde, Subramanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Yoo-Jin UNSPECIFIED UNSPECIFIED UNSPECIFIED Bohle, Rainer Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Juhasz-Boess, Ingolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Solomayer, Erich-Franz UNSPECIFIED UNSPECIFIED UNSPECIFIED Smola, Sigrun UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-152438
DOI:	10.1158/0008-5472.CAN-18-1913
Journal or Publication Title:	Cancer Res.
Volume:	79
Number:	7
Page Range:	S. 1573 - 1587
Date:	2019
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SQUAMOUS INTRAEPITHELIAL LESIONS; GROWTH-FACTOR-BETA; GENE-EXPRESSION; KAPPA-B; IL-12 PRODUCTION; T-CELLS; CYTOKINES; DIFFERENTIATION; INTERLEUKIN-6; ACTIVATION Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15243