90 | wetenschapsdag 2023 Sessie 3b: Chirurgie Voorbij de Scalpel x1 Auteurs L.M. Behrens, T. van den Berg, M. van Egmond Abstract titel Targeting the innate immune checkpoint CD47-SIRPα on neutrophils to potentiate antibody therapy Background In the last decades, different methods have been developed to harness the immune system for the treatment of cancer. One way to effectively stimulate an anti-tumor response is by the use of tumor-specific monoclonal antibodies (mAbs). These mAbs specifically bind to tumor antigens and are recognized by different immune cells. Neutrophils have been shown to kill antibodyopsonized tumor cells. However, neutrophil effector functions are limited by the inhibitory receptor SIRPα, when it interacts with CD47. Tumor cells often overexpress CD47 and thereby prevent tumor elimination by these neutrophils. Methods Neutrophil-mediated tumor cell killing can be divided into different steps: 1. Recognition of tumor cells; 2. Membrane transfer from tumor cells to neutrophils; and 3. Tumor cell death. To investigate the effect of SIRPα signaling in neutrophils on tumor cell killing, CD47 was genetically removed from tumor cells, or the interaction between CD47 and SIRPα was blocked with a specific antibody. Subsequently, neutrophils and antibody-opsonized tumor cells were combined, and the different steps of neutrophil-mediated tumor cell killing were studied. Results In the absence of mAbs, neutrophils were unable to identify and bind tumor cells. However, by opsonizing tumors with tumorspecific mAbs, neutrophils could recognize the tumor cells as target cells. Specific binding of neutrophils to these tumor cells allows them to nibble small pieces of tumor membrane through a process called trogocytosis. This eventually results in tumor cell death. Genetic removal of CD47 from tumor cells led to more interactions between neutrophils and tumor cells. These neutrophils then also acquired more tumor membrane fragments via trogocytosis, inducing more tumor cell death. Blocking the interaction between CD47-SIRPα with antibodies showed similar results. Conclusion Taken together, these results demonstrate that blocking the interaction between CD47 on tumor cells and the inhibitory receptor SIRPα on neutrophils promotes neutrophil-mediated cytotoxicity towards mAb-opsonized tumor cells.
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