Grant: CIHR Fellowship

Ovarian cancer is the most lethal gynecologic malignancy and treatment strategies have remained largely unchanged for decades. Immune checkpoint inhibitors (ICI) show impressive clinical efficacy in several cancers, yet the response in ovarian cancer has been limited. This is likely due to a hostile tumour microenvironment, characterized by disrupted blood flow, reduced oxygen, and factors that inhibit the tumour's immune response. Tumour-promoting macrophages, the most abundant immune cell type in ovarian tumours, elicit immune suppression, metastasis, and poor patient outcomes. Targeting tumour-promoting macrophages in ovarian cancer may improve ICI treatment efficacy and patient outcomes. Previously, our lab has shown that Fc3TSR, a fragment of the thrombospondin-1 protein, reduces lipid metabolism of ovarian cancer cells, induces cancer cell death, and facilitates cancer therapy uptake, ultimately leading to tumour regression in ovarian cancer. We will test whether targeting tumour-promoting macrophages in ovarian cancer improves ICI therapy response. Our goal is to evaluate the ability of Fc3TSR to 1) remodel the immunosuppressive tumour microenvironment by reprogramming macrophages to an anti-tumour phenotype, and 2) enhance the efficacy of ICI in translational, patient-derived organoid models of ovarian cancer. Our hypothesis is that Fc3TSR will suppress lipid metabolism in macrophages that is required for their differentiation toward a pro-tumour phenotype. We anticipate that the re-education of tumour-promoting macrophages will reduce immune suppression of the tumour microenvironment, enhance the infiltration and function of tumoricidal immune cells, and regress tumour growth and metastasis, ultimately improving ICI therapy response and overall survival in advanced ovarian cancer. These findings could reveal a novel and promising combination treatment strategy to overcome barriers of immunotherapy success that may benefit a variety of cancer types.