Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis

Tumour antigen (TA)-targeting monoclonal antibody (mAb) therapies drive cancer cell elimination in large part by triggering macrophage phagocytosis. However, cancer cells evade phagocytosis by mechanisms that are incompletely understood. Here, we develop a platform for unbiased identification of factors that impede antibody-dependent cancer phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many novel regulators of susceptibility to ADCP, including the poorly characterized enzyme Adipocyte Plasma Membrane Associated Protein (APMAP). We find that loss of APMAP synergizes with TA-targeting mAbs and/or CD47-blocking mAbs to drive dramatically increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumor targeting mAbs to inhibit tumour growth in mice. Using genome-wide counter-screens in macrophages, we find that the G-protein coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a novel cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.