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

Abstract

Cervical cancer is a consequence of persistent infection with human papillomaviruses (HPV). Progression to malignancy is linked to an inflammatory microenvironment comprising T-helper-17 (Th17) cells, a T-cell subset with protumorigenic properties. Neoplastic cells express only low endogenous levels of the Th17 chemoattractant CCL20, and therefore, it is unclear how Th17 cells are recruited to the cervical cancer tissue. In this study, we demonstrate that CCL20 was predominantly expressed in the stroma of cervical squamous cell carcinomas in situ. This correlated with stromal infiltration of CD4 þ /IL17 þ cells and with advancing International Federation of Gynecology and Obstetrics (FIGO) stage. Furthermore, we show that cervical cancer cells instructed primary cervical fibroblasts to produce high levels of CCL20 and to attract CD4/IL17/CCR6-positive cells, generated in vitro, in a CCL20/CCR6-dependent manner. Further mechanistic investigations identified cervical cancer cell-derived IL6 as an important mediator of paracrine CCL20 induction at the promoter, mRNA, and protein level in fibroblasts. CCL20 was upregulated through the recently described CCAAT/enhancerbinding protein b (C/EBPb) pathway as shown with a dominantnegative version of C/EBPb and through siRNA-mediated knockdown. In summary, our study defines a novel molecular mechanism by which cervical neoplastic cells shape their local microenvironment by instructing fibroblasts to support Th17 cell infiltration in a paracrine IL6/C/EBPb-dependent manner. Th17 cells may in turn maintain chronic inflammation within highgrade cervical lesions to further promote cancer progression.Cancer Res; 75(24); 5248-59. Ó2015 AACR.

Down-regulation of miR-29b in carcinoma associated fibroblasts promotes cell growth and metastasis of breast cancer

“…There are reports shown that fibroblasts involve in the cross-talk of cancer cells and fibroblasts by secreting CCL2 [30–32], CCL5 [33], CXCL1 [34], CXCL6 [35], CXCL12 [36], IL6 [37], CXCL16 [38] and others [23–31]. In the study, we identified that CCL11 and CXCL14 were the target genes of miR-29b in fibroblasts.…”

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

“…Moreover, a higher sensitivity was also observed for the topoisomerase II inhibitor etoposide used in recurrent cervical cancer (30), indicating that the sensitization was not restricted to a single class of chemotherapeutic drugs. Although the IL6-/STAT3-pathways appear to be attractive pharmacologic targets to improve the immune microenvironment (9,10,17,18), our data suggest that one should be cautious to combine STAT3 inhibitors with cisplatin or etoposide in cervical cancer patients.…”

“…IL6 has a negative impact on the prognosis of a patient (16). We have shown that it mainly acts in a paracrine manner and creates a protumorigenic and immunosuppressive microenvironment (10,17,18). Cervical cancer cells display only low responses to autocrine IL6 due to low gp80 expression levels (15,19) but sgp80 can restore autocrine IL6 signaling and induce pronounced STAT3-binding activity (15).…”

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

“…There is a strong need for new therapeutic strategies in cervical cancer patients because HPV interferes with local immunity suppressing the expression of inflammatory cytokines and chemokines in infected cells (28). Immunostimulatory cytokines like CCL2 and CCL20 are induced in the stromal compartment of invasive cervical carcinoma but they are involved in the generation of a pro-tumorigenic microenvironment (29)(30)(31). In contrast, the regulator of the adaptive immunity interleukin-12 is down-regulated in the cervical cancer microenvironment [own unpublished data and (32,33)].…”