Project 460419

Cancer immunotherapy has revolutionized cancer care, but its efficacy is dependent on the presence and activity of T cells within the tumor. We have discovered a unique immune cell type that consumes fat (lipids) from its surroundings, called "lipid-laden macrophages" (LLM). These LLM impair the ability of T cells to access tumors, and reduce their ability to mediate immunotherapy efficacy. Therefore, people who have a lot of LLM in their tumors are less likely to respond to immunotherapy. Our proposal will explore how LLM accumulate in tumors, and how they negatively regulate response to immunotherapy in ovarian, breast and prostate cancer. Using mouse models and patient samples, we will first study where LLM get fats from, and how these fats change their maturation and behaviour. We will then explore whether diet can be used to manipulate fat availability for LLM, and whether this in turn influences T cell function. Finally, we will explore whether targeting LLM can be combined with immunotherapy to enhance therapy efficacy. Obesity (high body mass index) is one of the leading risk factors for all cancer related mortalities, estimated to be responsible for up to 20% of all cancer deaths. Moreover, weight is an intersectional determinant of health inequities, and leveraging diet to improve cancer therapy may reduce health disparities. These studies will help explain the relationship between diet, cancer progression and therapy response, and are clinically relevant to a substantial proportion of the adult population.