Cervical Cancer–Instructed Stromal Fibroblasts Enhance IL23 Expression in Dendritic Cells to Support Expansion of Th17 Cells

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 þ 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 b (C/EBPb)-dependent induction of IL1b. 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/ EBPb/IL1b-dependent manner, thereby supporting the expansion of Th17 cells during cancer progression.

Immune deviation and cervical carcinogenesis

“…Unable to migrate, they produce pro-tumorigenic MMP-9 locally within the stroma [12]. Moreover, they secrete only low amounts of the Th1-polarizing cytokine IL-12 [18] potentially underlying the Th2 shift observed in cervical carcinogenesis in vivo. This indicates that deviated dendritic cells may rather contribute to tumor progression than to immune control.…”

“…Although their exact role is still unclear, the fact that they accumulate with advanced disease stages indicates a role in cancer progression [11]. The interplay between cervical cancer-instructed fibroblasts and dendritic cells further promotes expansion of Th17 cells via the heterodimeric cytokine IL-23 [18]. Interestingly, the cytokines IL-23 and IL-12 sharing the same IL-12p40 subunit are regulated by IL-6 in an opposing manner.…”

“…Interestingly, the cytokines IL-23 and IL-12 sharing the same IL-12p40 subunit are regulated by IL-6 in an opposing manner. While the IL-12-specific p35 subunit is directly suppressed by IL-6 in the dendritic cells, the IL-23-specific subunit p19 is indirectly induced by IL-6 via C/EBPβ-dependent IL-1β induction in the fibroblasts [18]. This further underscores the importance of IL-6 signaling for the establishment of chronic pro-tumorigenic inflammation and immune deviation in cervical carcinogenesis.…”

The combined action of monocytic myeloid‐derived suppressor cells and mucosal‐associated invariant T cells promotes the progression of cervical cancer

“…Numerous studies have reported that a local and/or systemic immunosuppressive microenvironment leads to the evasion of immune surveillance and promotes the development of cervical cancer 5‐15 . Some studies have indicated that an elevated level of patient‐derived immunosuppressive cells, such as T helper 17 (TH17) cells, myeloid‐derived suppressor cells (MDSCs) and regulatory T cells (Tregs), play a vital role in promoting cervical cancer progression 11‐15 . In addition, alterations in the levels or activity of CD4 + /CD8 + T cells and B cells have been suggested to be important in the immunological pathogenesis of cervical cancer 16‐18 .…”

Immunotherapy for HPV associated cancer

“…Resistance to cytotoxic T cell-mediated lysis may follow down regulation of tumour cell antigen processing or MHC expression [19]. Additionally, HPV transformed cells modulate the local immune environment to suppress effector immune responses by a wide range of mechanisms including induction from fibroblasts of immunomodulatory cytokines [20], induction of local innate M2 macrophages [21], and induction of antigen specific regulatory T cells [22]. There are thus substantial barriers to successful HPV protein targeted immunotherapy for naturally arising HPV associated malignancies in humans.…”