Characterisation of the myeloid compartment in ovarian cancer

O'Neill, Danielle (2022). Characterisation of the myeloid compartment in ovarian cancer. University of Birmingham. M.D.

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Abstract

This research was conducted to interrogate the myeloid compartment of the immune response within the tumour microenvironment of ovarian cancer and its metastatic sites. Despite the advances in the surgical approach of managing ovarian cancer, the prognosis remains dismal, highlighting the urgent need to develop immunotherapeutic agents to control disease progression and prevent relapse. Little is currently known about the myeloid compartment in ovarian cancer, and as such this thesis focuses upon these cells to fully phenotype and characterise the cells present in the primary site of ovarian cancer but also its secondary metastatic sites. This work demonstrated the presence of myeloid-derived suppressor cells (MDSC) in both benign and malignant neoplasms, a finding that has not been demonstrated previously. It was also shown that the ratio of granulocytic to monocytic MDSC was more predictive of underlying pathology, with high-grade serous ovarian cancer having a much greater ratio compared to healthy donors. Further functional characterisation of these MDSC was then performed in order to demonstrate their immunosuppressive function, where it was demonstrated that there were potential flaws within the laboratory technique of suppression assays. It was shown that MDSC have a great phagocytic capability, which led to phagocytosis of the Dynabeads thus affecting their ability to cause T cell proliferation and demonstrating an inaccurate immunosuppressive effect. Further suppression analyses demonstrated a lack of consistent immunosuppression and as such their phenotypic characterisation was sought through their gene expression using single cell RNA sequencing. The myeloid cells were identified through their unique genetic signatures and a cluster of MDSC-like cells were identified and were found to be in greatest number in the ovarian cancer specimens compared to the metastatic adenocarcinoma and normal samples. They were shown to have an upregulation in arginine and S100A8, both known to have a role in immunosuppression, which may suggest that these MDSC may serve a function in causing immunosuppression despite being unable to demonstrate this experimentally. This may suggest MDSC as a potential therapeutic target within ovarian cancer, however further functional work needs to be done in order to validate these findings.

Type of Work:

Thesis (Doctorates > M.D.)

Award Type:

Doctorates > M.D.

Supervisor(s):