The effect of chemotherapy on immune cells in the tumour microenvironment of high-grade serous ovarian cancer

Abstract

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 TGFR 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.