Thesis Dieke van Rees

Summary

Neutrophils, or granulocytes, are white blood cells that are not only able to fight microbial infections, but can also kill cancer cells given the right circumstances. Neutrophils can kill antibody-opsonized cancer cells through trogocytosis, a process in which the neutrophil takes up pieces of tumor cell membrane until it lyses and undergoes necrosis (trogo means ‘gnaw’ in Greek). Trogocytosis is a well-known mechanism to aid membrane-transfer between (immune) cells, but in the current context, neutrophil trogocytosis can have a lytic outcome. This thesis describes neutrophil trogocytic killing (trogoptosis) of various cancer cell types and its enhancement through the combination of tumor-targeting antibodies and CD47-SIRPα checkpoint blockade.
Different aspects of neutrophil trogocytosis are being described or investigated in this thesis. We summarized the various inhibitory immunoreceptors expressed on neutrophils, as well as their function in health and disease. We found that stimulating neutrophils with G-CSF or GM-CSF enhanced the level of trogocytosis and killing of neuroblastoma cells, but also found that this, combined with CD47-SIRPα checkpoint blockade was still insufficient to kill chronic lymphocytic leukemia (CLL) cells. Although neutrophils seem in general well-capable of killing cancer cells derived from solid tumors, CLL cells seem largely resistant. We found a way to overcome this by combining CD47-SIRPα blockade with sodium stibogluconate, a tyrosine phosphatase inhibitor. Finally, we investigated the capacity of cancer cells to repair their plasma membrane upon neutrophil trogocytosis and found that the exocyst complex is responsible for the repair of neutrophil trogocytosis-induced damage.