Neutrophil cytotoxic granules in microbial infection and cancer. (LSBR 1223))
Project leader: Prof. Dr. Timo K. van den Berg, Dept. of Blood Cell Research, Sanquin Research, Amsterdam
PhD student: Louise Treffers (Jan. 2014 – Jan. 2018)
Research technician: Paul Verkuijlen (June 2015 – June 2017)
Of all white blood cells the (neutrophilic) granulocytes are most abundant in our blood. Granulocytes play a crucial part in the defense against bacteria and fungal infections. This is illustrated by the notion that a decrease in numbers of granulocytes and defects in function lead to a strong increase in sensitivity towards such infections. In this project we tried to clarify the precise pathways of the killing of bacteria and fungi by granulocytes. We found that granulocytes use a variety of anti-bacterial and anti-fungal components that are stored in the granules in the cytoplasma of the cells. Whenever a bacterium or fungus is recognized, these granules are released or fuse with the phagosome, a vesicle-containing part of bacteria or fungi presented by other white blood cells (neutrophils). The bacteria or fungi will be killed by the contents of the granules and, in doing so, contribute to overcome the infection.
We also investigated whether neutrophilic granulocytes could play a role in the defense against cancer. We found that these cells are particularly effective in killing cancer cells in the presence of antibodies against the cancer cells. These antibodies are already available as therapeutic products for several types of cancer, such as breast cancer, colon cancer and lymphoma. The present research showed that neutrophilic granulocytes kill the cancer cells in a special and unique way not described thus far. The cells take little bites out of the cancer cells and in doing so tear apart the cancer cells in a proces we now call trogoptosis (‘trogo’ being Greek for gnaw). Furthermore we found that this process can be enhanced by disruption a natural break on the process known as the innate immune CD47-SIRPα checkpoint. Currently we are exploring this development of a new class of cancer therapeutic products against this innate immune CD47-SIRPα checkpoint that enhance the effect of the therapeutic antibodies against cancer. We, and others, hope to improve cancer treatment of relevant populations of patients. Our future plan is to investigate if mobilization of granulocuytes from bone marrow, using G-CSF, or transfusion with granulocytes could also improve the effect of cancer therapeutic antibodies.