Background: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown inBRCA1mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germlineBRCA1mutation in the context of cancer immunosurveillance of CD3−CD56+natural killer (NK) cells. Methods: PremenopausalBRCA1mutation carriers versus age-matched non-carriers were compared. Daily urinary 5β-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. Results:BRCA1mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly inBRCA1mutation carriers, reflecting a site-specific ‘hypoxic niche’. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. Conclusions: Phase-specific differential NK cell activity inBRCA1mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.
背景：在携带BRCA1突变的个体中，输卵管卵巢癌发生的组织特异性机制在很大程度上仍不明确。本研究旨在评估在CD3−CD56+自然杀伤（NK）细胞的癌症免疫监视背景下，种系BRCA1突变的细胞自主性与非自主性影响。方法：研究比较了绝经前BRCA1突变携带者与年龄匹配的非携带者。通过每日尿液5β-孕烷二醇水平测定卵巢周期中孕酮代谢组学特征。利用外周血获取的NK细胞，通过活细胞阻抗技术（xCELLigence®）和多色流式细胞术测定其对肿瘤靶细胞（OVCAR-3、K-562）的细胞介导毒性。对无癌输卵管标本进行缺氧诱导因子1α（HIF-1α）免疫组化分析，比较近端与远端部分的差异。基于这些发现，研究以卵巢周期阶段特异性方式，探讨了与输卵管伞端相关的环境因素（孕酮、缺氧）对NK细胞功能活性的影响。结果：BRCA1突变携带者表现出差异化的孕酮代谢组特征，并伴有外周NK细胞功能活性的阶段特异性降低。孕酮暴露以剂量依赖方式进一步损害NK细胞介导的细胞毒性，而添加米非司酮（1.25 µM）可逆转此效应。输卵管伞端显示显著更高的HIF-1α染色强度（尤其在BRCA1突变携带者中），反映了该部位特异的“缺氧微环境”。暴露于低氧条件（1% O2）可进一步损害高风险携带者的肿瘤细胞毒性功能。结论：BRCA1突变携带者体内系统性或局部存在的阶段特异性NK细胞活性差异，可能促进特定部位的浸润前癌变过程。这些效应在高风险携带者生殖生命周期中的累积影响具有危害性，进一步为抑制排卵的流行病学证据提供了理论支持。
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