Inhibition of Tumor Microenvironment Cytokine Signaling Sensitizes Ovarian Cancer Cells to Antiestrogen Therapy

SIMPLE SUMMARY: Antiestrogen hormonal therapy is a relatively low side effect, orally administered cancer treatment option, yet response rates have been limited in epithelial ovarian cancer despite estrogen receptor expression in many tumors. This suggests that other pathways impact estrogen response. Cytokine signaling from the tumor microenvironment promotes ovarian cancer growth, and crosstalk between cytokine signaling and estrogen signaling has been reported in other tumor types. We therefore aimed to investigate whether cytokine signaling impacts estrogen signaling in high-grade serous ovarian cancer. We demonstrated crosstalk between these two pathways in patient-derived samples, in vitro and in animal studies. We found that inhibiting interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokine signaling activates estrogen signaling and blocking both pathways was synergistic in inhibiting tumor cell growth. These results suggest a potential role for combination therapy for epithelial ovarian cancer patients. ABSTRACT: Antiestrogen therapy (AET) is an alternative to cytotoxic chemotherapy for recurrent ovarian cancer, yet the often short duration of response suggests mechanisms of resistance. We previously demonstrated that tumor microenvironment interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokines induce tumor cell JAK-STAT signaling to promote cancer growth. Crosstalk between estrogen signaling and cytokine signaling has been reported. Therefore, we sought to characterize the impact of IL6/LIF signaling on estrogen signaling in epithelial ovarian cancer and investigate the efficacy of combination therapy. We first assessed patient tumors for cytokine expression and compared it with response to AET to determine clinical relevance. In vitro, we determined the effect of IL6/LIF on estrogen receptor expression and signaling. Cell viability assays were used to determine the efficacy and potential synergy of cytokine blockade and AET. We then extended studies to animal models, incorporating patient-derived stromal cells. Our results demonstrated shorter progression-free interval on AET in patients with stromal IL6/LIF expression. In vitro, IL6/LIF increased tumor cell estrogen receptor expression and signaling, and combination cytokine blockade and AET resulted in synergistic inhibition of tumor cell growth. The anticancer effect was verified in a mouse model. In conclusion, due to crosstalk between IL6/LIF cytokine signaling and estrogen signaling, dual blockade is a potential new treatment approach for ovarian cancer.