Cervical cancer-instructed stromal fibroblasts enhance IL-23 expression in dendritic cells to support expansion of Th17 cells

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 T-helper-17 (Th17) cell recruitment, a cell type with pro-tumorigenic properties. In this study we analysed the expression of the Th17-promoting cytokine Interleukin(IL)-23 in the cervical cancer micromilieu and found CD83+ mature dendritic cells (mDC) co-expressing IL-23 in the stroma of cervical squamous cell carcinomas in situ. This expression of IL-23 correlated with stromal Th17 cells, advanced tumor stage, lymph node metastasis, and cervical cancers recurrence. Co-cultures of cervical cancer-instructed mDC and cervical fibroblasts led to potent pro-tumorigenic expansion of Th17 cells in vitro but failed to induce anti-tumor Th1 differentiation. Correspondingly, cervical cancer-instructed fibroblasts increased IL-23 production in co-cultured cervical cancer-instructed mDC, which mediated subsequent Th17 cell expansion. In contrast, production of the Th1-polarizing cytokine IL-12 in cancer-instructed mDC was strongly reduced. This differential IL-23 and IL-12 regulation was the consequence of an increased expression of IL-23 subunits IL-23p19 and IL-12p40 but decreased expression of the IL-12 subunit IL-12p35 in cervical cancer-instructed mDC. Cervical cancer cell-derived IL-6 directly suppressed IL-12p35 in mDC but indirectly induced IL-23 expression in fibroblasts-primed mDC via CAAT/enhancer-binding protein β (C/EBPβ)-dependent induction of IL-1β. In summary, our study defines a mechanism by which the cervical cancer micromilieu supports IL-23-mediated Th17 expansion associated with cancer progression.

http://bit.ly/2Th8OCc