Understanding and harnessing macrophage phagocytosis to eliminate disease-causing cells

Macrophages are immune cells that specialize in an ancient cell biological process called phagocytosis: the uptake of particulate matter or other cells. Phagocytosis is critical for all animal life, either as a means of feeding or to maintain homeostasis through clearance of disease-causing material. In humans, macrophages are present in all tissues, and destroy more than 200 billion aberrant cells every day via phagocytosis. Nevertheless, as we age, aberrant cells accumulate and give rise to a wide range of diseases including cancer, neurodegeneration, and atherosclerosis. Why macrophages fail to clear unwanted cells in the context of age-related diseases is not known. Despite our incomplete knowledge, therapies have been developed that can be used to treat disease by stimulating macrophages to precisely eliminate specific cell populations from the body. These therapies have transformed treatment outcomes in some diseases, including a subset of lymphomas. However, macrophage-based immunotherapies are critically limited in most cancers by the ability of tumor cells to suppress macrophage phagocytosis via mechanisms that are largely unknown.

Our work is driven equally by curiosity about the many forms and functions of phagocytosis in nature and the urgent need to develop new treatments for people suffering from incurable diseases. Some of the questions we are interested in are:

  • How do macrophages discern between healthy and abnormal cells?

  • What are the barriers to macrophage-mediated clearance of cancer cells and how can we overcome them therapeutically?

To answer these questions, we combine powerful genetic screening approaches to discover molecules that regulate macrophage function with biochemical, cell biological, and in vivo experiments to understand how these components work at a mechanistic level. We are particularly interested in genes, metabolites, and processes that have never been studied before and which may point us to entirely new avenues for disease intervention.