Haran, Shaun;
(2023)
The cell autonomous and cell-nonautonomous immunomodulation of natural killer cells in BRCA mutation carriers as a mechanism for ovarian carcinogenesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Germline BRCA1 mutation carriers are disproportionately at risk of developing ovarian cancers that arise from extra-uterine Müllerian sites, such as the fimbrial fallopian tube. The tissue specificity for this site remains unknown. Beyond the cellular contribution to dysfunctional DNA repair attributable to a BRCA1 mutation there are likely other contributing mechanisms. Natural killer (NK) cells represent a core component of protective host tumour immunosurveillance. Relative to other conventional cytotoxic or prototypic adaptive lymphocytes NK cells rapidly induce a robust functional response towards cancer targets. Determining baseline functionality and the potential scope for immunobiological modulation within sites of interest is vital in understanding mechanisms for potential ‘immune escape’, which is highly relevant for high-grade serous ovarian cancer (HGSOC) pathogenesis at the fimbrial fallopian tube. Here, NK cell activity is described in premenopausal women taking a methodical approach to ascertain baseline functionality of circulating NK cells in an attempt to mimic exposure effects specific to the fimbrial microenvironment. HGSOC cytotoxicity is shown to be differential based on ovarian cycle phase and cell autonomous presence of a BRCA1 mutation. Direct exposure to mediators aberrantly released in carriers (hypoxia, supra-physiological concentrations of progesterone) further abrogates anti-tumour activity. Alterations in a host cytokinome or secretory profile may contribute to findings relevant to NK cell activation and responses to tumour targets. Exposure to cyclical periods of reduced NK cell activity across the reproductive lifetime of a premenopausal BRCA1 mutation carrier may in turn support site-specific tumorigenic events via cancer immune invasion, making these findings highly relevant in understanding HGSOC carcinogenesis.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The cell autonomous and cell-nonautonomous immunomodulation of natural killer cells in BRCA mutation carriers as a mechanism for ovarian carcinogenesis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Natural killer cells, BRCA, Ovarian cancer |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10180509 |
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