Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic cancer. Emerging evidence suggests that tumor-associated macrophages (TAMs) play an immunosuppressive role in the tumor microenvironment and promote tumor growth, angiogenesis, and metastasis in ovarian cancer. Therefore, targeting TAMs in patients with ovarian cancer is an appealing strategy; however, all trials to date have failed. To improve the efficacy of this approach, we sought to elucidate the underlying mechanisms of the role of TAMs in ovarian cancer. We found that the developmental transcription factor GATA3 was highly expressed in HGSOC cell lines but not in the fallopian tube, which is the main origin of HGSOC. GATA3 expression was associated with poor prognosis in HGSOC patients (P < .05) and was found to promote proliferation and migration in HGSOC cell lines. GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment. Moreover, GATA3 acted as a regulator for macrophage polarization and interactions between TAMs and HGSOC to support proliferation, motility, and cisplatin chemoresistance in mutant TP53 HGSOC cell lines. Furthermore, GATA3 played a critical role in the interactions between TAMs and mutant TP53 HGSOC to promote angiogenesis and epithelial-mesenchymal transition with epigenetic regulation. Targeting GATA3 using GATA3siRNA in TAMs impeded GATA3-driven proliferation, migration, cisplatin chemoresistance, and angiogenesis in mutant TP53 HGSOC cell lines. Our findings indicate that GATA3 plays a novel role in immunoediting of HGSOC and demonstrate that GATA3 may serve as a prognostic marker for HGSOC and a promising target in the treatment of HGSOC.
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•Expression of TAMs markers is often associated with poor clinical outcome in HGSOC patients.•GATA3 is highly expressed in HGSOC patients but not in the fallopian tube, the main origin of HGSOC.•GATA3 act as oncogenic protein in HGSOC patients.•GATA3 was released abundantly from TAM cells via exosomes and contributed to tumor growth in the tumor microenvironment.•GATA3 is a master regulator for macrophage polarization and interactions between TAMs and HGSOC.•TAMs-Exosomal-GATA3 was supported proliferation, motility, angiogenesis and cisplatin-chemoresistance in mutant-TP53 HGSOC.•GATA3 plays a novel role in immuno-editing of HGSOC.•GATA3 is a promising target to eradicate HGSOC in the future.•GATA3 acted as tumor suppressor in endometrial cancer.