Grunewald, Tami; (2024) Ovarian Cancer and the Immune Tumour Microenvironment. Doctoral thesis (M.D(Res)), UCL (University College London).

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Abstract

Epithelial ovarian cancer (EOC) is the leading cause of gynaecological cancer deaths worldwide. Most women present with advanced disease and whilst the majority of patients respond to primary treatment, most will relapse and eventually develop chemotherapy resistance. New treatment strategies are urgently needed. I implemented a phase II clinical trial (PROMPT) exploring whether maintenance immunotherapy (pembrolizumab) improved progression free survival (PFS) in patients with platinum resistant ovarian cancer, who have stable disease / response to weekly paclitaxel. The 6-month PFS rate was 5.0%. Median PFS was 2.0 months and overall survival (OS) 9.8 months. The trial did not meet its primary end point and was closed early due to futility. I interrogated the ovarian cancer immune microenvironment using blood and tumour samples from patients with high grade ovarian cancer treated at University College London Hospital (UCLH) between October 2020 and June 2021. Blood was collected at various timepoints, processed into peripheral blood mononuclear cells (PBMCs) and frozen. They were later analysed using flow cytometry; two panels exploring T- and myeloid cells. Where available, formalin-fixed paraffin-embedded (FFPE) tissue blocks were collected and analysed using three multiplex immunofluorescence (mIF) panels. I found changes in circulating immune cells of patients; specifically increased numbers of regulatory T-cells (Tregs), with overexpression of TIM-3 and PD-1 when compared to age- and gender-matched healthy donors (HD). I also observed a reduction in circulating classical monocytes following chemotherapy, particularly in patients with worse outcomes. Within the tumour, I found a reduction in the number of CD4+ TIM- 3+ +/- PD-1+ T-cells and increased numbers of macrophages in patients with a poorer prognosis. These results highlight the complexity of the immune microenvironment in ovarian cancer. It is difficult to interpret the clinical implications of these findings, but this research provides a foundation for future work in identifying prognostic and predictive biomarkers in EOC.

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