Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis

Shaun Haran; Kantaraja Chindera; May Sabry; Nafisa Wilkinson; Rupali Arora; Agnieszka Zubiak; Thomas E Bartlett; Iona Evans; Allison Jones; Daniel Reisel; Chiara Herzog; Twana Alkasalias; Mark Newman; Jaeyeon Kim; Angelique Flöter Rådestad; Kristina Gemzell-Danielsson; Adam N Rosenthal; Louis Dubeau; Mark W Lowdell; Martin Widschwendter

doi:10.3390/cancers16061186

Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis

Cancers (Basel). 2024 Mar 18;16(6):1186. doi: 10.3390/cancers16061186.

Authors

Shaun Haran^{1

2}, Kantaraja Chindera¹, May Sabry³, Nafisa Wilkinson⁴, Rupali Arora⁴, Agnieszka Zubiak³, Thomas E Bartlett⁵, Iona Evans¹, Allison Jones¹, Daniel Reisel¹, Chiara Herzog^{6

7}, Twana Alkasalias^{8

9}, Mark Newman¹⁰, Jaeyeon Kim¹¹, Angelique Flöter Rådestad⁸, Kristina Gemzell-Danielsson⁸, Adam N Rosenthal^{1

2}, Louis Dubeau¹², Mark W Lowdell³, Martin Widschwendter^{1

6

7

8}

Affiliations

¹ Department of Women's Cancer, Elizabeth Garrett Anderson (EGA) Institute for Women's Health, University College London (UCL), 72 Huntley Street, London WC1E 6DD, UK.
² Department of Gynaeoncology, University College London Hospitals (UCLH) NHS Trust, London NW1 2BU, UK.
³ Institute of Immunity & Transplantation, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, UK.
⁴ Department of Cellular Pathology, University College London Hospitals (UCLH) NHS Trust, London NW1 2BU, UK.
⁵ Department of Statistical Science, University College London, London WC1E 7HB, UK.
⁶ European Translational Oncology Prevention and Screening (EUTOPS) Institute, University of Innsbruck, 6060 Hall in Tirol, Austria.
⁷ Research Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
⁸ Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden.
⁹ General Directorate of Scientific Research Center, Salahaddin University-Erbil, Erbil 44002, Iraq.
¹⁰ Precision Analytical Inc., McMinnville, OR 97128, USA.
¹¹ Department of Biochemistry and Molecular Biology, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
¹² Department of Pathology, Keck School of Medicine, USC Norris Comprehensive Cancer Centre, University of Southern California, Los Angeles, CA 90033, USA.

Abstract

Background: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3^- CD56⁺ natural killer (NK) cells.

Methods: Premenopausal BRCA1 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: BRCA1 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 BRCA1 mutation 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 in BRCA1 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.

Keywords: BRCA1; epithelial ovarian cancer; immune surveillance; natural killer cells.

Grants and funding

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Program (grant agreement No 742432; BRCA-ERC) and The Eve Appeal (https://eveappeal.org.uk (accessed on 1 September 2017)). Author T.A. declared funding from Lena Wäppling’s Foundation 2023. Author J.K. declared funding from The U.S. Department of Defense W81XWH2210390. No external funders were involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.