Interrogating the relationship between the tumour microenvironment and its infiltrating immune cells in ovarian cancer

Pounds, Rachel Louise (2023). Interrogating the relationship between the tumour microenvironment and its infiltrating immune cells in ovarian cancer. University of Birmingham. Ph.D.

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Abstract

Ovarian cancer (OC) is the sixth most common cancer amongst women, with approximately 7,500 new cases diagnosed each year in the United Kingdom. The complex ovarian tumour microenvironment is poorly understood, while the nature and role of tumour-infiltrating NK cells in OC progression remains unclear. To analyse the cell type contexture of OC tissue, two single cell sequencing techniques were performed on omental tumour biopsies from patients with advanced OC. The scRNAseq analysis focused on portraying an immunogenic tumour microenvironment and determined the characteristics of a dysfunctional NK cell population, implying NK reactivation upon chemotherapy exposure. In contrast, scATACseq data identified significant epithelial tumour cell heterogeneity and demonstrated an increase in chromatin accessibility for oncogenes and transcription factors related to cancer stem cells following chemotherapy treatment. Utilising a large prospective cohort of OC patient samples, the phenotype and function of NK cells in peripheral blood, primary ovarian tumour and metastatic omental tumour was explored. Flow cytometric analysis has revealed that peripheral blood NK cells are activated in OC, while NK cell inhibition occurs following tumour infiltration. Results have shown the adaptations to NK cell receptors in advancing disease and the specific inhibitory NK features associated with poor patient outcomes. The OC NK cells demonstrated a reduced ability to proliferate and expand upon exposure to cells lacking HLA and secreted fewer cytokines than the non-cancerous control samples. Instead, the OC NK cells were highly cytotoxic towards K-562 cells and primary ovarian tumours. Interestingly, the NK cell cytotoxicity to primary ovarian tumours was dependent on the activation receptor, DNAM-1. The significance of DNAM-1 in the tumour-immune response was demonstrated, identifying it as a possible biomarker that can be used as a target for NK-mediated immunotherapy.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):