- Title
- The role of immune cells in ovarian cancer
- Creator
- Ahmady, Farah
- Date
- 2022
- Type
- Text; Thesis; PhD
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/184111
- Identifier
- vital:16415
- Abstract
- Ovarian cancer remains the leading cause of gynaecological disease related death in women worldwide. Patients given standard treatment have low survival rates and immunotherapy remains unsuccessful. This is largely due to the suppressive tumour microenvironment (TME) and the interaction of the different cells being poorly understood. This has sparked interest in understanding the functions of immune cells and their contribution to the TME. In chapter 3, B and T cells were characterised in samples collected from chemo-naïve highgrade serous ovarian cancer (HGSOC) patients and compared to benign and healthy controls. B cells were able to express the T cell exhaustion marker T cell immunoglobulin and mucin domain-3 (TIM-3) on their surface. Blood derived B cells of benign patients expressed less TIM-3 compared to high-grade and healthy donors. Alterations in TIM-3 expression on B cells suggests that the TME may not be causing B cells to harbour an exhaustion phenotype. The frequency of circulating mucosal-associated invariant T cells (MAIT cells) was reduced in benign and high-grade patients compared to healthy donors. Blood derived MAIT cells of healthy donors stimulated with 5-OP-RU antigen and cultured with ovarian cancer cell line supernatants had a reduced capacity of producing tumour necrosis factor (TNF)-a compared to control. The reduced frequency of MAIT cells at the premalignant state of the disease indicates that malignancy of the disease is not necessarily the contributing factor in the reduction observed. As TNF-a is a key anti-tumour cytokine expressed by MAIT cells, the impaired production may indicate defects in their function. Low dose-dense (LDD) chemotherapy has recently shown promise as depicted in a clinical study by Kannourakis et al. where LDD treated HGSOC patients had longer survival than those treated with maximum tolerated dose (MTD). It is postulated that this may be due to aspects of the immune system, however the effects of LDD chemotherapy on immune cells remains unknown. In chpter 4, circulating B and T cells of LDD treated patients were characterised and compared to untreated controls. The key finding of this study was the immunostimulatory attributes of LDD regimen in a range of B and T cell populations via their increased expression of TNF-a compared to untreated controls and healthy donors. The frequency of MAIT cells, however, was reduced in LDD treated patients, suggesting that these cells may not contribute to the immunostimulatory aspects, and that this regimen may impact their frequency by creating an environment which may not be compatible for MAIT cell survival. In chapter 5, expression of immuno-oncology protein markers in benign and high-grade primary and metastasised tumours were determined for alterations in hot and cold tumour regions using Digital Spatial Profiling (DSP). An increased expression of immune cell, costimulatory and inhibitory markers were apparent in high-grade tumours compared to benign. The stimulator of interferon genes (STING) marker was studied further, and its expression was also higher in high-grade tumours compared to benign, with cisplatin further enhancing its expression in ovarian cancer cell lines. There were alterations in the expression of some downstream molecules, however interferon (IFN)-b, the key cytokine produced in the activated STING pathway, was virtually non-existent. This suggests a defect in the pathway which if restored, may contribute to some of the known anti-tumour functions of the pathway. The results from these studies provide an understanding of differences in the immune profile of non-malignant and malignant ovarian cancer. These findings work together to improve our understanding of the unique TME with the aim to identify potential immune therapeutic targets for future study.; Doctor of Philosophy
- Publisher
- Federation University Australia
- Rights
- All metadata describing materials held in, or linked to, the repository is freely available under a CC0 licence
- Rights
- Copyright Farah Ahmady
- Rights
- Open Access
- Subject
- Ovarian cancer; Tumour microenvironment; Immune cells; Immunotherapy
- Full Text
- Thesis Supervisor
- Ahmed, Nuzhat
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