The effects of neo-adjuvant chemotherapy on myeloid cells in high-grade serous ovarian cancer metastases. (360G-Wellcome-201118_Z_16_Z)

Many tumours have abundant macrophage populations. Tumour-associated macrophages (TAMs) frequently have tumour promoting roles and high levels are associated with poor clinical outcome. In mouse cancer models chemotherapy appears to increase TAM density. Furthermore, macrophage depletion improves response to chemotherapy in breast cancer models. The host lab has studied the effects of neo-adjuvant chemotherapy (NACT) on T-cell responses in high-grade serous ovarian cancer (HGSOC) patients and shown potential enhancement of the host anti-tumour immune response following NACT. However, we do not know the effect of chemotherapy on TAMs in these patients. We hypothesise that targeting the recruitment, polarization and effector function of TAMs may improve HGSOC response to chemotherapy as well as having independent anti-cancer activity. We will characterise TAMs in HGSOC pre and post NACT using human samples and mouse models. Anticipating significant heterogeneity of TAM populations we will employ single-cell and whole myeloid population RNA-sequencing to define the major macrophage populations in HGSOC pre and post NACT. These results will be validated using flow cytometry and immunohistochemistry. We will test the effects of chemotherapy and macrophage-targeting agents on TAM populations and tumour response in mouse HGSOC models. Our aim is that these results will translate to clinical trial.