Natural Killer Cell Dysfunction in Premenopausal Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis.

Background: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline mutation in the context of cancer immunosurveillance of CD3 CD56 natural killer (NK) cells.

Methods: Premenopausal mutation 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: mutation 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 in mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O) can further impair tumor cytotoxicity in high-risk carriers.

Conclusions: Phase-specific differential NK cell activity in mutation 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.