The aim of this thesis was to understand the immune modulatory effects of chemotherapy in high-grade serous ovarian cancer (HGSOC). Using single cell RNA sequencing (scRNAseq) I studied the immune landscape of HGSOC omental metastasis from seven patients (three prechemotherapy and four postchemotherapy) with analysis of 64,097 cells in total. I also conducted scRNAseq on 69,781 cells from a HGSOC mouse model that is characterised clinically by marginal response to chemotherapy and transcriptionally by high TGF. The model replicated most of the human immune cell subpopulations. Chemotherapy enhanced host anti-tumour immune response pathways in human and mouse immune cells but this effect was counterbalanced by other immune-inhibitory effects in the same cell populations. I hypothesised that these inhibitory pathways could be targeted to improve response to chemotherapy. I found significant upregulation of the macrophage scavenger receptor Stabilin-1 postchemotherapy in human and mouse tumours. Blocking Stabilin-1 in vitro resulted in significant increase in TNF secretion by macrophages. Combining an anti-stabilin1 antibody with chemotherapy in the HGSOC mouse model led to a significant increase in overall survival compared to chemotherapy alone. Furthermore, it had some efficacy as a monotherapy. Response to the anti-stabilin1 plus chemotherapy combination was associated with the formation of lymphoid aggregates and a significant increase in CD8 T cell infiltrate. I also identified two immunosuppressive effects of chemotherapy on T cells: upregulation of FOXP3 and the TGF pathway. After some in vitro validation, I combined a FOXP3 or TGFR inhibitor with chemotherapy in the model. This also led to a significant increase in median survival over chemotherapy alone but neither of these inhibitors were effective as monotherapies. Overall, my results provide preliminary evidence for using novel immunotherapies to induce a more durable response to chemotherapy and prolong survival with a rationale for simultaneously targeting both macrophages and T cells
