title: Interferon-Gamma Receptor Signaling Plays an Important Role in Restraining Murine Ovarian Tumor Progression.
abstract: Immune cell-derived cytotoxic pathways have been implicated in antitumor immune responses. The goal of this study is to characterize how these cytotoxic pathways influence ovarian cancer development. We have utilized the TgMISIIR-TAg transgenic mouse model which expresses the transforming SV40 TAg in the ovary, leading to spontaneous development of ovarian tumors that closely mimic human epithelial ovarian cancer. To test how perforin (Prf1), granzyme B (GzmB) and interferon-gamma (IFNg) impact tumor occurrence and progression, we bred the TgMISIIR-TAg transgene intoPrf1-/-,GzmB-/-, andIFNgR1-/-mice. The transgenic females developed peritoneal tumors at 9-15 weeks and succumbed at 184 ± 37 days of age with 100% penetrance (n=41). Knockout of these cytotoxic genes does not affect tumor occurrence. However, loss of function in the IFNg signaling pathway significantly expedited tumor progression with all of theIFNg R1-/-TgMISIIR-TAg females succumbing to tumor outgrowth at 167 ± 27 days of age (p=0.0074, n=24). In contrast, loss of function of Prf1 or GzmB did not significantly impact tumor progression and host survival. Since tumor cells in theIFNg R1-/-TgMISIIR-TAg mice areIFNg R1deficient, we used the implantable MOSEC (mouse ovarian surface epithelial cell) tumor line to validate thatIFNg Rsignaling in host immune cells but not in tumor cells impacts tumor progression. Indeed, when the IFNg -responsive MOSEC cells were inoculated,IFNg R1-/-mice exhibited significantly higher tumor burden compared to WT mice. Furthermore, a MOSEC-splenocyte co-culture system confirmed thatIFNg R1-/-immune cells were less effective than WT immune cells in controlling MOSEC tumor growthin vitro. Together, these results indicate that theIFNg Rsignaling pathway plays an important role in restraining murine ovarian tumor progression.
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Guanglin
authors: G
authors: Bian
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Nicholas D
authors: ND
authors: Leigh
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Wei
authors: W
authors: Du
authors: The fourth affiliated hospital, Hebei Medical University, Shijiazhuang, China.
authors: Lei
authors: L
authors: Zhang
authors: The fourth affiliated hospital, Hebei Medical University, Shijiazhuang, China.
authors: Li
authors: L
authors: Li
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, USA.
authors: Xuefang
authors: X
authors: Cao
keywords: Cytotoxic pathways; Granzyme B (GzmB); Interferon-gamma (IFNg); Ovarian cancer; Perforin (Prf1); Tumor immunity