EXPLORING THE DYNAMIC RELATIONSHIPS BETWEEN NATURAL KILLER CELLS AND HIGH GRADE SEROUS OVARIAN CARCINOMAS

Abstract

High-grade serous carcinoma of the ovary (HGSC) is the deadliest gynecologic malignancy and, unfortunately, treatment options and survival rates have remained stagnant over the past four decades. Challenged by extreme intra- and inter- tumoural heterogeneity, loss of HLA expression, and an immunosuppressive microenvironment, existing immunotherapies have benefited few patients. Natural killer (NK) cells may be ideal cellular therapies performing cytokine production and cytotoxicity prompted by heterogeneous signals including stress, DNA damage, inflammation, HLA loss, and bound antibodies. There are numerous strategies to enhance NK cells through immunotherapy, including immune-stimulating adjuvants, antibody-mediated strategies, genetic engineering, or adoptive cell transfers. However, the knowledge required to design these therapies effectively is lacking. In my PhD program, I investigated the relationship between NK cells and HGSC by first conducting a systematic review and meta-analysis that revealed that NK cell infiltration correlates with improved survival in solid tumours, noting that the trends were unclear in ovarian cancer. To explore a potential association more definitively in HGSC, I developed a custom immunofluorescence panel to analyze NK cell presence and distribution in solid HGSC tumours. I discovered that NK cells often co-infiltrate tumours and co-localize with other immune cells like T cells and macrophages with these groups associating with response to therapy and overall survival. Finally, using single-cell RNA sequencing data, I identified five NK cell populations in treatment-naïve HGSC samples, shedding light on their heterogeneity and their associations with specific features of HGSC. This thesis has contributed to understanding the impact, localization, and transcriptional state of NK cells in HGSC. These findings are critical for developing more precise NK cell-based immunotherapies.